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Purpose: To systematically investigate kinetic metrics and metabolic trapping of [13N]NH3 in organs. Methods: Eleven participants performed total-body [13N]NH3 dynamic positron emission tomography (PET). Regions of interest were drawn in organs to obtain time-to-activity curves (TACs), which were fitted with an irreversible two-tissue compartment model (2TC) to investigate constant rates K1, k2 and k3, and to calculate Ki. Additionally, one-tissue compartment model using full data (1TCfull) and the first four minutes of data (1TC4min) were fitted to TAC data. K1 and k2 were compared among different models to assess [13N]NH3 trapping in organs. Results: Kinetic rates of [13N]NH3 varied significantly among organs. The mean K1 ranged from 0.049 mL/cm3/min in the muscle to 2.936 mL/cm3/min in the kidney. The k2 and k3 were lowest in the liver (0.001 min− 1) and in the pituitary (0.009 min− 1), while highest in the kidney (0.587 min− 1) and in the liver (0.800 min− 1), respectively. The Ki was largest in the myocardium (0.601 ± 0.259 mL/cm3/min) while smallest in the bone marrow (0.028 ± 0.022 mL/cm3/min). Three groups of organs with similar kinetic characteristics were revealed: (1) the thyroid, the lung, the spleen, the pancreas, and the kidney; (2) the liver and the muscle; and (3) the cortex, the white matter, the cerebellum, the pituitary, the parotid, the submandibular gland, the myocardium, the bone, and the bone marrow. Obvious k3 was identified in multiple organs, and significant changes of K1 in multiple organs and k2 in most organs were found between 2TC and 1TCfull, but both K1 and k2 were comparable between 2TC and 1TC4min. Conclusion: The kinetic rates of [13N]NH3 differed among organs with some have obvious 13N-anmmonia trapping. The normal distribution of kinetic metrics of 13N-anmmonia in organs can serve as a reference for its potential use in tumor imaging. [ABSTRACT FROM AUTHOR]

There is limited information on utilizing commercially supplied [18F]Fluoride from an off-site cyclotron for the synthesis of radiopharmaceuticals. This study explored the production of the PET hypoxia marker [18F]FMISO, using the Scintomics® GRP module and distantly produced [18F]Fluoride, which lacks published data. A radiochemical yield of 27.4 ± 3.6% (n = 5) and high radiochemical purity were achieved in synthesis time of 48 min. The [18F]FMISO met all Ph. Eur. standards, demonstrating the consistency and reliability of the module in generating a clinical-grade radiopharmaceutical using off-site produced [18F]Fluoride, but available patient doses were severely limited. [ABSTRACT FROM AUTHOR]

This study aimed to develop several new machine learning models based on hibernating myocardium to predict the major adverse cardiac events(MACE) of ischemic left ventricular systolic dysfunction(LVSD) patients receiving either percutaneous coronary intervention(PCI) or optimal medical therapy(OMT). This study included 329 LVSD patients, who were randomly assigned to the training or validation cohort. Least absolute shrinkage and selection operator(LASSO) regression was used to identify variables associated with MACE. Subsequently, various machine learning models were established. Model performance was compared using receiver operating characteristic(ROC) curves, the Brier score(BS), and the concordance index(C-index). A total of 329 LVSD patients were retrospectively enrolled between January 2016 and December 2021. Utilizing LASSO regression analysis, five factors were selected. Based on these factors, RSF, GBM, XGBoost, Cox, and DeepSurv models were constructed. In the development and validation cohorts, the C-indices were 0.888 vs. 0.955 (RSF). The RSF model (0.991 vs. 0.982 vs. 0.980) had the highest area under the ROC curve (AUC) compared with the other models. The BS (0.077 vs. 0.095vs. 0.077) of RSF model were less than 0.25 at 12, 18, and 24 months. This study developed a novel predictive model based on RSF to predict MACE in LVSD patients who underwent either PCI or OMT. [ABSTRACT FROM AUTHOR]

A new type of hybrid polymer particles capable of carrying the cytostatic drug doxorubicin and labeled with a gallium compound was prepared. These microparticles consist of a core and a hydrogel shell, which serves as the structural matrix. The shell can be employed to immobilize gallium oxide hydroxide (GaOOH) nanoparticles and the drug, resulting in hybrid beads with sizes of approximately 3.81 ± 0.09 μm. The microparticles exhibit the ability to incorporate a remarkably large amount of doxorubicin, approximately 0.96 mg per 1 mg of the polymeric carrier. Additionally, GaOOH nanoparticles can be deposited within the hydrogel layer at an amount of 0.64 mg per 1 mg of the carrier. These nanoparticles, resembling rice grains with an average size of 593 nm by 155 nm, are located on the surface of the polymer carrier. In vitro studies on breast and colon cancer cell lines revealed a pronounced cytotoxic effect of the hybrid polymer particles loaded with doxorubicin, indicating their potential for cancer therapies. Furthermore, investigations on doping the hybrid particles with the Ga-68 radioisotope demonstrated their potential application in positron emission tomography (PET) imaging. The proposed structures present a promising theranostic platform, where particles could be employed in anticancer therapies while monitoring their accumulation in the body using PET. [ABSTRACT FROM AUTHOR]

Purpose: Accumulating evidence suggests that neurotensin (NTS) and neurotensin receptors (NTSRs) play key roles in lung cancer progression by triggering multiple oncogenic signaling pathways. This study aims to develop Cu-labeled neurotensin receptor 1 (NTSR1)-targeting agents with the potential for both imaging and therapeutic applications. Method: A series of neurotensin receptor antagonists (NRAs) with variable propylamine (PA) linker length and different chelators were synthesized, including [64Cu]Cu-CB-TE2A-iPA-NRA ([64Cu]Cu-4a-c, i = 1, 2, 3), [64Cu]Cu-NOTA-2PA-NRA ([64Cu]Cu-4d), [64Cu]Cu-DOTA-2PA-NRA ([64Cu]Cu-4e, also known as [64Cu]Cu-3BP-227), and [64Cu]Cu-DOTA-VS-2PA-NRA ([64Cu]Cu-4f). The series of small animal PET/CT were conducted in H1299 lung cancer model. The expression profile of NTSR1 was also confirmed by IHC using patient tissue samples. Results: For most of the compounds studied, PET/CT showed prominent tumor uptake and high tumor-to-background contrast, but the tumor retention was strongly influenced by the chelators used. For previously reported 4e, [64Cu]Cu-labeled derivative showed initial high tumor uptake accompanied by rapid tumor washout at 24 h. The newly developed [64Cu]Cu-4d and [64Cu]Cu-4f demonstrated good tumor uptake and tumor-to-background contrast at early time points, but were less promising in tumor retention. In contrast, our lead compound [64Cu]Cu-4b demonstrated 9.57 ± 1.35, 9.44 ± 2.38 and 9.72 ± 4.89%ID/g tumor uptake at 4, 24, and 48 h p.i., respectively. Moderate liver uptake (11.97 ± 3.85, 9.80 ± 3.63, and 7.72 ± 4.68%ID/g at 4, 24, and 48 h p.i.) was observed with low uptake in most other organs. The PA linker was found to have a significant effect on drug distribution. Compared to [64Cu]Cu-4b, [64Cu]Cu-4a had a lower background, including a greatly reduced liver uptake, while the tumor uptake was only moderately reduced. Meanwhile, [64Cu]Cu-4c showed increased uptake in both the tumor and the liver. The clinical relevance of NTSR1 was also demonstrated by the elevated tumor expression in patient tissue samples. Conclusions: Through the side-by-side comparison, [64Cu]Cu-4b was identified as the lead agent for further evaluation based on its high and sustained tumor uptake and moderate liver uptake. It can not only be used to efficiently detect NTSR1 expression in lung cancer (for diagnosis, patient screening, and treatment monitoring), but also has the great potential to treat NTSR-positive lesions once chelating to the beta emitter 67Cu. [ABSTRACT FROM AUTHOR]

Deep learning, particularly convolutional neural networks (CNNs), has advanced positron emission tomography (PET) image reconstruction. However, it requires extensive, high-quality training datasets. Unsupervised learning methods, such as deep image prior (DIP), have shown promise for PET image reconstruction. Although DIP-based PET image reconstruction methods demonstrate superior performance, they involve highly time-consuming calculations. This study proposed a two-step optimization method to accelerate end-to-end DIP-based PET image reconstruction and improve PET image quality. The proposed two-step method comprised a pre-training step using conditional DIP denoising, followed by an end-to-end reconstruction step with fine-tuning. Evaluations using Monte Carlo simulation data demonstrated that the proposed two-step method significantly reduced the computation time and improved the image quality, thereby rendering it a practical and efficient approach for end-to-end DIP-based PET image reconstruction. [ABSTRACT FROM AUTHOR]

Objective: Positron Emission Tomography (PET) is a well-known imaging technology for the diagnosis, treatment, and monitoring of several diseases. Most PET scanners use a Ring-Shaped Detector Configuration (RSDC), which helps obtain homogeneous image quality but are restricted to an invariable Field-of-View (FOV), scarce spatial resolution, and low sensitivity. Alternatively, few PET systems use Open Detector Configurations (ODC) to permit an accessible FOV adaptable to different target sizes, thus optimizing sensitivity. Yet, to compensate the lack of angular coverage in ODC-PET, developing a detector with high-timing performance is mandatory to enable Time-of-Flight (TOF) techniques during reconstruction. The main goal of this work is to provide a proof of concept PET scanner appropriate for constructing the new generation of ODC-PET suitable for biopsy guidance and clinical intervention during acquisition. The designed detector has to be compact and robust, and its requirements in terms of performance are spatial and time resolutions < 2 mm and < 200 ps, respectively. Methods: The present work includes a simulation study of an ODC-PET based on 2-panels with variable distance. The image quality (IQ) and Derenzo phantoms have been simulated and evaluated. The phantom simulations have also been performed using a ring-shaped PET for comparison purposes of the ODC approach with conventional systems. Then, an experimental evaluation of a prototype detector that has been designed following the simulation results is presented. This study focused on tuning the ASIC parameters and evaluating the scintillator surface treatment (ESR and TiO2), and configuration that yields the best Coincidence Time Resolution (CTR). Moreover, the scalability of the prototype to a module of 64 × 64mm2 and its preliminary evaluation regarding pixel identification are provided. Results: The simulation results reported sensitivity (%) values at the center of the FOV of 1.96, 1.63, and 1.18 for panel distances of 200, 250, and 300 mm, respectively. The IQ reconstructed image reported good uniformity (87%) and optimal CRC values, and the Derenzo phantom reconstruction suggests a system resolution of 1.6–2 mm. The experimental results demonstrate that using TiO2 coating yielded better detector performance than ESR. Acquired data was filtered by applying an energy window of ± 30% at the photopeak level. After filtering, best CTR of 230 ± 2 ps was achieved for an 8 × 8 LYSO pixel block with 2 × 2 × 12mm3 each. The detector performance remained constant after scaling-up the prototype to a module of 64 × 64mm2, and the flood map demonstrates the module's capabilities to distinguish the small pixels; thus, a spatial resolution < 2 mm (pixel size) is achieved. Conclusions: The simulated results of this biplanar scanner show high performance in terms of image quality and sensitivity. These results are comparable to state-of-the-art PET technology and, demonstrate that including TOF information minimizes the image artifacts due to the lack of angular projections. The experimental results concluded that using TiO2 coating provide the best performance. The results suggest that this scanner may be suitable for organ study, breast, prostate, or cardiac applications, with good uniformity and CRC. [ABSTRACT FROM AUTHOR]

An automated method has been developed for the synthesis of [N-methyl-11C]choline, a radiopharmaceutical (RP) for the diagnosis of cancer using positron emission tomography (PET). The synthesis was carried out on a home-made module, using combined technology of on-line 11C-methylation processes and solid-phase extraction methods. The radiochemical yield of [N-methyl-11C]choline was 80% (based on the activity of the methylating agent, [11C]CH3I, decay corrected), which ensures the production of several clinical doses of radiopharmaceutical in one batch. [N-Methyl-11C]choline was obtained with a radiochemical purity of more than 99% and an amount of 2-dimethylaminoethanol (the main chemical impurity) of 0.06 mg/mL, which meets the requirements of the Russian and European Pharmacopoeia. [ABSTRACT FROM AUTHOR]

Background: Accurately redirecting reconstructed Positron emission tomography (PET) images into short-axis (SA) images shows great significance for subsequent clinical diagnosis. We developed a system for automatic redirection and quantitative analysis of myocardial PET images. Methods: A total of 128 patients were enrolled for 18 F-FDG PET/CT myocardial metabolic images (MMIs), including 3 image classifications: without defects, with defects, and excess uptake. The automatic reorientation system includes five modules: regional division, myocardial segmentation, ellipsoid fitting, image rotation and quantitative analysis. First, the left ventricular geometry-based canny edge detection (LVG-CED) was developed and compared with the other 5 common region segmentation algorithms, the optimized partitioning was determined based on partition success rate. Then, 9 myocardial segmentation methods and 4 ellipsoid fitting methods were combined to derive 36 cross combinations for diagnostic performance in terms of Pearson correlation coefficient (PCC), Kendall correlation coefficient (KCC), Spearman correlation coefficient (SCC), and determination coefficient. Finally, the deflection angles were computed by ellipsoid fitting and the SA images were derived by affine transformation. Furthermore, the polar maps were used for quantitative analysis of SA images, and the redirection effects of 3 different image classifications were analyzed using correlation coefficients. Results: On the dataset, LVG-CED outperformed other methods in the regional division module with a 100% success rate. In 36 cross combinations, PSO-FCM and LLS-SVD performed the best in terms of correlation coefficient. The linear results indicate that our algorithm (LVG-CED, PSO-FCM, and LLS-SVD) has good consistency with the reference manual method. In quantitative analysis, the similarities between our method and the reference manual method were higher than 96% at 17 segments. Moreover, our method demonstrated excellent performance in all 3 image classifications. Conclusion: Our algorithm system could realize accurate automatic reorientation and quantitative analysis of PET MMIs, which is also effective for images suffering from interference. [ABSTRACT FROM AUTHOR]

Purpose: A series of new 68Ga-labeled tracers based on [68Ga]Ga-PSMA-617 were developed to augment the tumor-to-kidney ratio and reduce the activity accumulation in bladder, ultimately minimize radiation toxicity to the urinary system. Methods: We introduced quinoline group, phenylalanine and decanoic acid into different tracers to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Their binding affinity onto LNCaP cells was determined through in vitro saturation assays and competition binding assays. In vivo metabolic study, PET imaging and biodistribution experiment were performed in LNCaP tumor-bearing B-NSG male mice. The most promising tracer was selected for first-in-human study. Results: Four radiotracers were synthesized with radiochemical purity (RCP) > 95% and molar activity in a range of 20.0-25.5 GBq/μmol. The binding affinities (Ki) of TWS01, TWS02 to PSMA were in the low nanomolar range (< 10 nM), while TWS03 and TWS04 exhibited binding affinities with Ki > 20 nM (59.42 nM for TWS03 and 37.14 nM for TWS04). All radiotracers exhibited high stability in vivo except [68Ga]Ga-TWS03. Micro PET/CT imaging and biodistribution analysis revealed that [68Ga]Ga-TWS02 enabled clear tumor visualization in PET images at 1.5 h post-injection, with higher tumor-to-kidney ratio (T/K, 0.93) and tumor-to-muscle ratio (T/M, 107.62) compared with [68Ga]Ga-PSMA-617 (T/K: 0.39, T/M: 15.01) and [68Ga]Ga-PSMA-11 (T/K: 0.15, T/M: 24.00). In first-in-human study, [68Ga]Ga-TWS02 effectively detected PCa-associated lesions including primary and metastatic lesions, with lower accumulation in urinary system, suggesting that [68Ga]Ga-TWS02 might be applied in the detection of bladder invasion, with minimized radiation toxicity to the urinary system. Conclusion: Introduction of quinoline group, phenylalanine and decanoic acid into different tracers can modulate the binding affinity and pharmacokinetics of PSMA in vivo. [68Ga]Ga-TWS02 showed high binding affinity to PSMA, excellent pharmacokinetic properties and clear imaging of PCa-associated lesions, making it a promising radiotracer for the clinical diagnosis of PCa. Moreover, TWS02 with a chelator DOTA could also label 177Lu and 225Ac, which could be used for PCa treatment without significant side effects. Trial registration: The clinical evaluation of this study was registered On October 30, 2021 at https://www.chictr.org.cn/ (No: ChiCTR2100052545). [ABSTRACT FROM AUTHOR]

Background: Residual image noise is substantial in positron emission tomography (PET) and one of the factors limiting lesion detection, quantification, and overall image quality. Thus, improving noise reduction remains of considerable interest. This is especially true for respiratory-gated PET investigations. The only broadly used approach for noise reduction in PET imaging has been the application of low-pass filters, usually Gaussians, which however leads to loss of spatial resolution and increased partial volume effects affecting detectability of small lesions and quantitative data evaluation. The bilateral filter (BF) — a locally adaptive image filter — allows to reduce image noise while preserving well defined object edges but manual optimization of the filter parameters for a given PET scan can be tedious and time-consuming, hampering its clinical use. In this work we have investigated to what extent a suitable deep learning based approach can resolve this issue by training a suitable network with the target of reproducing the results of manually adjusted case-specific bilateral filtering. Methods: Altogether, 69 respiratory-gated clinical PET/CT scans with three different tracers ( [ 18 F ] FDG, [ 18 F ] L-DOPA, [ 68 Ga ] DOTATATE) were used for the present investigation. Prior to data processing, the gated data sets were split, resulting in a total of 552 single-gate image volumes. For each of these image volumes, four 3D ROIs were delineated: one ROI for image noise assessment and three ROIs for focal uptake (e.g. tumor lesions) measurements at different target/background contrast levels. An automated procedure was used to perform a brute force search of the two-dimensional BF parameter space for each data set to identify the "optimal" filter parameters to generate user-approved ground truth input data consisting of pairs of original and optimally BF filtered images. For reproducing the optimal BF filtering, we employed a modified 3D U-Net CNN incorporating residual learning principle. The network training and evaluation was performed using a 5-fold cross-validation scheme. The influence of filtering on lesion SUV quantification and image noise level was assessed by calculating absolute and fractional differences between the CNN, manual BF, or original (STD) data sets in the previously defined ROIs. Results: The automated procedure used for filter parameter determination chose adequate filter parameters for the majority of the data sets with only 19 patient data sets requiring manual tuning. Evaluation of the focal uptake ROIs revealed that CNN as well as BF based filtering essentially maintain the focal SUV max values of the unfiltered images with a low mean ± SD difference of δ SUV max CNN , STD = (−3.9 ± 5.2)% and δ SUV max BF , STD = (−4.4 ± 5.3)%. Regarding relative performance of CNN versus BF, both methods lead to very similar SUV max values in the vast majority of cases with an overall average difference of δ SUV max CNN , BF = (0.5 ± 4.8)%. Evaluation of the noise properties showed that CNN filtering mostly satisfactorily reproduces the noise level and characteristics of BF with δ Noise CNN , BF = (5.6 ± 10.5)%. No significant tracer dependent differences between CNN and BF were observed. Conclusions: Our results show that a neural network based denoising can reproduce the results of a case by case optimized BF in a fully automated way. Apart from rare cases it led to images of practically identical quality regarding noise level, edge preservation, and signal recovery. We believe such a network might proof especially useful in the context of improved motion correction of respiratory-gated PET studies but could also help to establish BF-equivalent edge-preserving CNN filtering in clinical PET since it obviates time consuming manual BF parameter tuning. [ABSTRACT FROM AUTHOR]

Purpose: Neuropilin-1 (NRP-1) is a multifunctional protein involved in a variety of biological processes such as angiogenesis, tumorigenesis and immunomodulation. It was usually overexpressed in many cancer cell lines and correlated with poor prognosis of breast cancer. Positron emission tomography (PET) is an advanced imaging technique for detecting the function and metabolism of tumor-associated molecules in real time, dynamically, quantitatively and noninvasively. To improve the level of early diagnosis and evaluate the prognosis of breast cancer, an NRP-1 targeting peptide-based tracer [68 Ga]Ga-NOTA-PEG4-CK2 was designed to sensitively and specifically detect the NRP-1 expression in vivo via PET imaging. Methods: In silico modeling and microscale thermophoresis (MST) assay were carried out to design the NRP-1 targeting peptide NOTA-PEG4-CK2, and it was further radiolabeled with 68 Ga to prepare the tracer [68 Ga]Ga-NOTA-PEG4-CK2. The radiochemical yield (RCY), radiochemical purity (RCP), molar activity (Am), lipid-water partition coefficient (Log P) and stability of [68 Ga]Ga-NOTA-PEG4-CK2 were assessed. The targeting specificity of the tracer for NRP-1 was investigated by in vitro cellular uptake assay and in vivo PET imaging as well as blocking studies. The sensitivity of the tracer in monitoring the dynamic changes of NRP-1 expression induced by chemical drug was also investigated in vitro and in vivo. Ex vivo biodistribution, autoradiography, western blot, and immunofluorescence staining were also performed to study the specificity of [68 Ga]Ga-NOTA-PEG4-CK2 for NRP-1. Results: [68 Ga]Ga-NOTA-PEG4-CK2 was designed and synthesized with high RCY (> 98%), high stability (RCP > 95%) and high affinity to NRP-1 (KD = 25.39 ± 1.65 nM). In vitro cellular uptake assay showed that the tracer [68 Ga]Ga-NOTA-PEG4-CK2 can specifically bind to NRP-1 positive cancer cells MDA-MB-231 (1.04 ± 0.04% at 2 h) rather than NRP-1 negative cancer cells NCI-H1299 (0.43 ± 0.05%). In vivo PET imaging showed the maximum tumor uptake of [68 Ga]Ga-NOTA-PEG4-CK2 in MDA-MB-231 xenografts (4.16 ± 0.67%ID/mL) was significantly higher than that in NCI-H1299 xenografts (1.03 ± 0.19%ID/mL) at 10 min post injection, and the former exhibited higher tumor-to-muscle uptake ratio (5.22 ± 0.18) than the latter (1.07 ± 0.27) at 60 min post injection. MDA-MB-231 xenografts pretreated with nonradioactive precursor NOTA-PEG4-CK2 showed little tumor uptake of [68 Ga]Ga-NOTA-PEG4-CK2 (1.67 ± 0.38%ID/mL at 10 min post injection). Both cellular uptake assay and PET imaging revealed that NRP-1 expression in breast cancer MDA-MB-231 could be effectively suppressed by SB-203580 treatment and can be sensitively detected by [68 Ga]Ga-NOTA-PEG4-CK2. Ex vivo analysis also proved the high specificity and sensitivity of [68 Ga]Ga-NOTA-PEG4-CK2 for NRP-1 expression in MDA-MB-231 xenografts. Conclusion: A promising NRP-1 targeting PET tracer [68 Ga]Ga-NOTA-PEG4-CK2 was successfully prepared. It showed remarkable specificity and sensitivity in monitoring the dynamic changes of NRP-1 expression. Hence, it could provide valuable information for early diagnosis of NRP-1 relevant cancers and evaluating the prognosis of cancer patients. A novel promising NRP-1 targeting PET tracer [68 Ga]Ga-NOTA-PEG4-CK2 was developed based on a series of in vitro and in vivo investigations. The tracer showed remarkable specificity and sensitivity in detecting the expression of NRP-1. It could be applied for noninvasively and dynamically monitoring the NRP-1 expression in tumors and predicting the prognosis of breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Triple-negative breast cancer (TNBC) has a poor prognosis due to the absence of effective therapeutic targets. Vascular endothelial growth factor (VEGF) family are expressed in 30–60% of TNBC, therefore providing potential therapeutic targets for TNBC. Aflibercept (Abe), a humanized recombinant fusion protein specifically bound to VEGF-A, B and placental growth factor (PIGF), has proven to be effective in the treatment in some cancers. Therefore, 89Zr/177Lu-labeled Abe was investigated for its theranostic role in TNBC. Methods: Abe was radiolabeled with 89Zr and 177Lu via the conjugation of chelators. Flow cytometry and cell immunofluorescent staining were performed to evaluate the binding affinity of Abe. Sequential PET imaging and fluorescent imaging were conducted in TNBC tumor bearing mice following the injection of 89Zr-labeled Abe and Cy5.5-labeled Abe. Treatment study was performed after the administration of 177Lu-labeled Abe. Tumor volume and survival were monitored and SPECT imaging and biodistribution studies were conducted. Safety evaluation was performed including body weight, blood cell measurement, and hematoxylin–eosin (H&E) staining of major organs. Expression of VEGF and CD31 was tested by immunohistochemical staining. Dosimetry was estimated using the OLINDA software. Results: FITC-labeled Abe showed a strong binding affinity to VEGF in TNBC 4T1 cells and HUVECs by flow cytometry and cell immunofluorescence. Tumor uptake of 89Zr-labeled Abe peaked at 120 h (SUVmax = 3.2 ± 0.64) and persisted before 168 h (SUVmax = 2.54 ± 0.42). The fluorescence intensity of the Cy5.5-labeled Abe group surpassed that of the Cy5.5-labeled IgG group, implying that Cy5.5-labeled Abe is a viable candidate monitoring in vivo tumor targeting and localization. 177Lu-labeled Abe (11.1 MBq) served well as the therapeutic component to suppress tumor growth with standardized tumor volume at 16 days, significantly smaller than PBS group (about 815.66 ± 3.58% vs 3646.52 ± 11.10%, n = 5, P < 0.01). Moreover, SPECT images confirmed high contrast between tumors and normal organs, indicating selective tumor uptake of 177Lu-labeled Abe. No discernible abnormalities in blood cells, and no evident histopathological abnormality observed in liver, spleen, and kidney. Immunohistochemical staining showed that 177Lu-labeled Abe effectively inhibited the expression of VEGF and CD31 of tumor, suggesting that angiogenesis may be suppressed by 177Lu-labeled Abe. The whole-body effective dose for an adult human was estimated to be 0.16 mSv/MBq. Conclusion: 89Zr/177Lu-labeled Abe could be a TNBC-specific marker with diagnostic value and provide insights into targeted therapy in the treatment of TNBC. Further clinical evaluation and translation may be of high significance for TNBC. [ABSTRACT FROM AUTHOR]

Purpose: To investigate and compare the dynamic positron emission tomography (PET) imaging with [18F]Alfatide II Imaging and [11C]Methionine ([11C]MET) in orthotopic rat models of glioblastoma multiforme (GBM), and to assess the utility of [18F]Alfatide II in detecting and evaluating neoangiogenesis in GBM. Methods: [18F]Alfatide II and [11C]MET were injected into the orthotopic GBM rat models (n = 20, C6 glioma cells), followed by dynamic PET/MR scans 21 days after surgery of tumor implantation. On the PET image with both radiotracers, the MRI-based volume-of-interest (VOI) was manually delineated encompassing glioblastoma. Time-activity curves were expressed as tumor-to-normal brain ratio (TNR) parameters and PET pharmacokinetic modeling (PKM) performed using 2-tissue-compartment models (2TCM). Immunofluorescent staining (IFS), western blotting and blocking experiment of tumor tissue were performed for the validation. Results: Compared to 11C-MET, [18F]Alfatide II presented a persistent accumulation in the tumor, albeit with a slightly lower SUVmean of 0.79 ± 0.25, and a reduced uptake in the contralateral normal brain tissue, respectively. This resulted in a markedly higher tumor-to-normal brain ratio (TNR) of 18.22 ± 1.91. The time–activity curve (TACs) showed a significant increase in radioactive uptake in tumor tissue, followed by a plateau phase up to 60 min for [18F]Alfatide II (time to peak:255 s) and 40 min for [11C]MET (time to peak:135 s) post injection. PKM confirmed significantly higher K1 (0.23/0.07) and K3 (0.26/0.09) in the tumor region compared to the normal brain with [18F]Alfatide II. Compared to [11C]MET imaging, PKM confirmed both significantly higher K1/K2 (1.24 ± 0.79/1.05 ± 0.39) and K3/K4 (11.93 ± 4.28/3.89 ± 1.29) in the tumor region with [18F]Alfatide II. IFS confirmed significant expression of integrin and tumor vascularization in tumor region. Conclusion: [18F]Alfatide II demonstrates potential in imaging tumor-associated neovascularization in the context of glioblastoma multiforme (GBM), suggesting its utility as a tool for further exploration in neovascular characterization. [ABSTRACT FROM AUTHOR]

Purpose: Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [11C]methionine PET/CT, [11C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan. Methods: We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99mTc-sestamibi. All patients underwent [11C]methionine PET/CT, [11C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6 months after surgery were used as gold standard for curation of HPT. Results: A total of 32 patients were included in the study. With blinded evaluation, [11C]choline PET/CT was positive in 28 patients (88%), [11C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [11C]choline PET/CT, [11C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [11C]choline PET/CT differed significantly from that of [11C]methionine PET/CT and 4D-CT (p = 0.031 and p < 0.0005, respectively). Conclusion: In the setting of pHPT with negative first-line imaging, [11C]choline PET/CT is superior to [11C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost–benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques. [ABSTRACT FROM AUTHOR]

A study published in the European Journal of Nuclear Medicine & Molecular Imaging explores the potential of STING-targeted PET imaging in monitoring tumor immunogenicity in colorectal cancer (CRC) patients after chemotherapy. The study uses a novel PET tracer called [18F]FBTA, which demonstrates higher specificity and sensitivity compared to conventional [18F]FDG. The research findings indicate that [18F]FBTA accurately reflects the impact of different chemotherapeutic agents on the immune activity of CRC tumors. The study suggests that [18F]FBTA holds promise as a reliable clinical tool for guiding treatment decisions and facilitating the combination of immunotherapy with chemotherapy in CRC patients. [Extracted from the article]

Purpose: Due to tumor heterogeneity, immunohistochemistry (IHC) showed poor accuracy in detecting the expression of programmed cell death ligand-1 (PD-L1) in patients. Positron emission tomography (PET) imaging is considered as a non-invasive technique to detect PD-L1 expression at the molecular level visually, real-timely and quantitatively. This study aimed to develop novel peptide-based radiotracers [68Ga]/[18F]AlF-NOTA-IMB for accurately detecting the PD-L1 expression and guiding the cancer immunotherapy. Methods: NOTA-IMB was prepared by connecting 2,2′-(7-(2-((2,5-dioxopyrrolidin-1-yl)oxy)- 2-oxoethyl)-1,4,7-triazonane-1,4-diyl) diacetic acid (NOTA-NHS) with PD-L1-targeted peptide IMB, and further radiolabeled with 68Ga or 18F-AlF. In vitro binding assay was conducted to confirm the ability of [68Ga]/[18F]AlF-NOTA-IMB to detect the expression of PD-L1. In vivo PET imaging of [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB in different tumor-bearing mice was performed, and dynamic changes of PD-L1 expression level induced by immunotherapy were monitored. Radioautography, western blotting, immunofluorescence staining and biodistribution analysis were carried out to further evaluate the specificity of radiotracers and efficacy of PD-L1 antibody immunotherapy. Results: [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB were both successfully prepared with high radiochemical yield (> 95% and > 60%, n = 5) and radiochemical purity (> 95% and > 98%, n = 5). Both tracers showed high affinity to human and murine PD-L1 with the dissociation constant (Kd) of 1.00 ± 0.16/1.09 ± 0.21 nM (A375-hPD-L1, n = 3) and 1.56 ± 0.58/1.21 ± 0.39 nM (MC38, n = 3), respectively. In vitro cell uptake assay revealed that both tracers can specifically bind to PD-L1 positive cancer cells A375-hPD-L1 and MC38 (5.45 ± 0.33/3.65 ± 0.15%AD and 5.87 ± 0.27/2.78 ± 0.08%AD at 120 min, n = 3). In vivo PET imaging and biodistribution analysis showed that the tracer [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB had high accumulation in A375-hPD-L1 and MC38 tumors, but low uptake in A375 tumor. Treatment of Atezolizumab induced dynamic changes of PD-L1 expression in MC38 tumor-bearing mice, and the tumor uptake of [68Ga]NOTA-IMB decreased from 3.30 ± 0.29%ID/mL to 1.58 ± 0.29%ID/mL (n = 3, P = 0.026) after five treatments. Similarly, the tumor uptake of [18F]AlF-NOTA-IMB decreased from 3.27 ± 0.63%ID/mL to 0.89 ± 0.18%ID/mL (n = 3, P = 0.0004) after five treatments. However, no significant difference was observed in the tumor uptake before and after PBS treatment. Biodistribution, radioautography, western blotting and immunofluorescence staining analysis further demonstrated that the expression level of PD-L1 in tumor-bearing mice treated with Atezolizumab significantly reduced about 3 times and correlated well with the PET imaging results. Conclusion: [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB were successfully prepared for PET imaging the PD-L1 expression noninvasively and quantitatively. Dynamic changes of PD-L1 expression caused by immunotherapy can be sensitively detected by both tracers. Hence, the peptide-based radiotracers [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB can be applied for accurately detecting the PD-L1 expression in different tumors and monitoring the efficacy of immunotherapy. Two novel peptide-based radiotracers [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB were developed as promising agents for evaluating the immunotherapy effect by monitoring the changes of PD-L1 expression in real time. [ABSTRACT FROM AUTHOR]

Purpose: Multiple system atrophy (MSA) is a rare neurodegenerative disease, often presented with orthostatic hypotension (OH), which is a disabling symptom but has not been very explored. Here, we investigated MSA patients with OH by using positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) and 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (11C-CFT) for in vivo evaluation of the glucose metabolism and dopaminergic function of the brain. Methods: Totally, 51 patients with MSA and 20 healthy controls (HC) who underwent 18F-FDG PET/CT were retrospectively enrolled, among which 24 patients also underwent 11C-CFT PET/CT. All patients were divided into MSA-OH(+) and MSA-OH(-) groups. Then, statistical parametric mapping (SPM) method was used to reveal the regional metabolic and dopaminergic characteristics of MSA-OH(+) compared with MSA-OH(-). Moreover, the metabolic networks of MSA-OH(+), MSA-OH(-) and HC groups were also constructed and analyzed based on graph theory to find possible network-level changes in MSA patients with OH. Results: The SPM results showed significant hypometabolism in the pons and right cerebellar tonsil, as well as hypermetabolism in the left parahippocampal gyrus and left superior temporal gyrus in MSA-OH(+) compared with MSA-OH(-). A reduced 11C-CFT uptake in the left caudate was also shown in MSA-OH(+) compared with MSA-OH(-). In the network analysis, significantly reduced local efficiency and clustering coefficient were shown in MSA-OH(+) compared with HC, and decreased nodal centrality in the frontal gyrus was found in MSA-OH(+) compared with MSA-OH(-). Conclusion: In this study, the changes in glucose metabolism in the pons, right cerebellar tonsil, left parahippocampal gyrus and left superior temporal gyrus were found closely related to OH in MSA patients. And the decreased presynaptic dopaminergic function in the left caudate may contribute to OH in MSA. Taken together, this study provided in vivo pathophysiologic information on MSA with OH from neuroimaging approach, which is essential for a better understanding of MSA with OH. [ABSTRACT FROM AUTHOR]

Purpose: Presynaptic dopaminergic positron emission tomography (PET) imaging serves as an essential tool in diagnosing and differentiating patients with suspected parkinsonism, including idiopathic Parkinson's disease (PD) and other neurodegenerative and non-neurodegenerative diseases. The PET tracers most commonly used at the present time mainly target dopamine transporters (DAT), aromatic amino acid decarboxylase (AADC), and vesicular monoamine type 2 (VMAT2). However, established standards for the imaging procedure and interpretation of presynaptic dopaminergic PET imaging are still lacking. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform presynaptic dopaminergic PET imaging. Method: A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for presynaptic dopaminergic PET imaging in parkinsonism, focusing on standardized recommendations, procedures, interpretation, and reporting. Conclusion: This international consensus and practice guideline will help to promote the standardized use of presynaptic dopaminergic PET imaging in parkinsonism. It will become an international standard for this purpose in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The demand for 68Ga-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, 68Ga-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([68Ga]Ga-FAPI-46) in late-phase studies, whereas [68Ga]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach. Results: Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 ± 5% for [68Ga]Ga-FAPI-46 and 46 ± 7% for [68Ga]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC were 98.2 ± 0.2% and 98.4 ± 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including 68Ga trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers. Conclusions: The microfluidic-based approach enabled the implementation of radiosynthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC on the iMiDEV™ microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2–3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [68Ga]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future. [ABSTRACT FROM AUTHOR]

Background: The apolipoprotein E-deficient (apoE−/−) mouse is a well-established model for studying atherosclerosis. However, its small size limits its use in longitudinal positron emission tomography (PET) imaging studies. Recently, the apoE−/− rat has emerged as an alternative. With this study, we investigate the feasibility of using apoE−/− rats as an in vivo model for longitudinal atherosclerotic PET/CT imaging. Results: ApoE−/− rats showed significantly higher [18F]FDG uptake than controls in the aortic arch (+ 18.5%, p < 0.001) and abdominal aorta (+ 31.0%, p < 0.001) at weeks 12, 26, and 51. ApoE−/− rats exhibited hypercholesterolemia, as evidenced by plasma cholesterol levels that were up to tenfold higher, and total hepatic cholesterol levels that were up to threefold higher than the control rats at the end of the study. Fast protein liquid chromatography cholesterol profiling indicated very high levels of pro-atherogenic apoB-containing very low-density lipoprotein and low-density lipoprotein fractions in the apoE−/− rats. Atherosclerotic lesions cover 19.9% of the surface of the aortic arch (p = 0.0013), and there was a significantly higher subendothelial accumulation of ED1-positive macrophages in the abdominal aorta of the apoE−/− rats compared to control rats (Ctrl) (p = 0.01). No differences in neutral sterols were observed but higher levels of bile acids were found in the apoE−/− rats. Conclusion: These data demonstrate early signs of hypercholesterolemia, high levels of bile acids, the development of atherosclerotic lesions, and macrophage accumulation in apoE−/− rats. Therefore, this model shows promise for atherosclerosis imaging studies. [ABSTRACT FROM AUTHOR]

3,4-Methylenedioxy-β-nitrostyrene (MNS) is an inhibitor of NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3) inflammasome. This inflammasome is a potential PET imaging target, because it is involved in the aggregation of amyloid-β and tau proteins in Alzheimer's disease brains. We succeeded in a challenging radio-synthesis of [11C]MNS using nitromethylenating piperonal with [11C]nitromethane (CH3NO2) in one pot. We then evaluated this ligand in rat brains. Although [11C]MNS had some moderate brain uptake and quick washout in rat brains, we were unable to detect any presence of specific binding of this ligand to NLRP3 either in vivo or in vitro. Further studies appear needed to develop more suitable radioligands for PET imaging of NLRP3. [ABSTRACT FROM AUTHOR]

Background: The positron emitting isotope fluorine-18 (18F) possesses almost ideal physicochemical properties for the development of radiotracers for diagnostic molecular imaging employing positron emission tomography (PET). 18F in its nucleophilic anionic 18F− form is usually prepared by bombarding an enriched 18O water target with protons of various energies between 5 and 20 MeV depending on the technical specifications of the cyclotron. Large thick-target yields between 5 and 14 GBq/µA can be obtained, enough to prepare large batches of radiotracers capable to serve a considerable contingent of patients (50 + per clinical batch). The overall yield of the radiotracer however depends on the efficiency of the 18F labeling chemistry. The Silicon Fluoride Acceptor chemistry (SiFA) has introduced a convenient and highly efficient way to provide clinical peptide-based 18F-radiotracers in a kit-like procedure matching the convenience of 99mTc radiopharmaceuticals. Main body: A radiotracer's clinical success primarily hinges on whether its synthesis can be automated. Due to its simplicity, the SiFA chemistry, which is based on isotopic exchange (18F for 19F), does not only work in a manual setup but has been proven to be automatable, yielding large batches of 18F-radiotracers of high molar activity (Am). The production of SiFA radiotracer can be centralized and the radiopharmaceutical be distributed via the "satellite" principle, where one production facility economically serves multiple clinical application sites. Clinically validated tracers such as [18F]SiTATE and [18F]Ga-rhPSMA-7/-7.3 have been synthesized in an automated synthesis unit under good manufacturing practice conditions and used in large patient cohorts. Communication of common guidelines and practices is warranted to further the dissemination of SiFA radiopharmaceuticals and to give easy access to this technology. Conclusion: This current review highlights the most recent achievements in SiFA radiopharmaceutical automation geared towards large batch production for clinical application. Best practice advice and guidance towards a facilitated implementation of the SiFA technology into new and already operating PET tracer production facilities is provided. A brief outlook spotlights the future potential of SiFA radiochemistry within the landscape of non-canonical labeling chemistries. [ABSTRACT FROM AUTHOR]

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Background: Pulsed-field ablation (PFA) is a novel ablation modality for atrial fibrillation (AF) ablating myocardium by electroporation without tissue-heating. With its different mechanism of tissue ablation, it is assumed that lesion creation is divergent to thermal energy sources. 68Ga-fibroblast-activation protein inhibitor (FAPI) PET/CT targets FAP-alpha expressed by activated fibroblasts. We aimed to assess 68Ga-FAPI uptake in pulmonary veins as surrogate for ablation damage after PFA and cryoballoon ablation (CBA). Methods: 26 patients (15 PFA, 11 CBA) underwent 68Ga-FAPI-PET/CT after ablation. Standardized uptake values (SUV) and fibroblast-activation volumes of localized tracer uptake were assessed. Results: Patient characteristics were comparable between groups. In PFA, focal FAPI uptake was only observed in 3/15 (20%) patients, whereas in the CBA cohort, 10/11 (90.9%) patients showed atrial visual uptake. We observed lower values of SUVmax (2.85 ± 0.56 vs 4.71 ± 2.06, P = 0.025) and FAV (1.13 ± 0.84 cm3 vs 3.91 ± 2.74 cm3, P = 0.014) along with a trend towards lower SUVpeak and SUVmean in PFA vs CBA patients, respectively. Conclusion: Tissue response with respect to fibroblast activation seems to be less pronounced in PFA compared to established thermal ablation systems. This functional assessment might contribute to a better understanding of lesion formation in thermal and PFA ablation potentially contributing to better safety outcomes. [ABSTRACT FROM AUTHOR]

Background: Composite invasive and non-invasive data consistently demonstrate that resting myocardial blood flow (rMBF) in regions of known transmural myocardial scar (TMS) converge on a value of ~ 0.30 mL/min/g or lower. This value has been confirmed using the 3 most common myocardial perfusion agents (13N, 15O-H2O and 82Rb) incorporating various kinetic models on older 2D positron emission tomography (PET) systems. Thus, rMBF in regions of TMS can serve as a reference "truth" to evaluate low-end accuracy of various PET systems and software packages (SWPs). Using 82Rb on a contemporary 3D-PET-CT system, we sought to determine whether currently available SWP can accurately and precisely measure rMBF in regions of known TMS. Results: Median rMBF (in mL/min/g) and COV in regions of TMS were 0.71 [IQR 0.52–1.02] and 0.16 with 4DM; 0.41 [0.34–0.54] and 0.10 with 4DM-FVD; 0.66 [0.51–0.85] and 0.11 with Cedars; 0.51 [0.43–0.61] and 0.08 with Emory-Votaw; 0.37 [0.30–0.42], 0.07 with Emory-Ottawa, and 0.26 [0.23–0.32], COV 0.07 with HeartSee. Conclusions: SWPs varied widely in low end accuracy based on measurement of rMBF in regions of known TMS. 3D PET using 82Rb and HeartSee software accurately (0.26 mL/min/g, consistent with established values) and precisely (COV = 0.07) quantified rMBF in regions of TMS. The Emory-Ottawa software yielded the next-best accuracy (0.37 mL/min/g), though rMBF was higher than established gold-standard values in ~ 5% of the resting scans. 4DM, 4DM-FDV, Cedars and Emory-Votaw SWP consistently resulted values higher than the established gold standard (0.71, 0.41, 0.66, 0.51 mL/min/g, respectively), with higher interscan variability (0.16, 0.11, 0.11, and 0.09, respectively). Trial registration: clinicaltrial.gov, NCT05286593, Registered December 28, 2021, https://clinicaltrials.gov/ct2/show/NCT05286593. [ABSTRACT FROM AUTHOR]

Background: The resistance of glioblastoma stem cells (GSCs) to treatment is one of the causes of glioblastoma (GBM) recurrence. Endothelin A receptor (ETA) overexpression in GSCs constitutes an attractive biomarker for targeting this cell subpopulation, as illustrated by several clinical trials evaluating the therapeutic efficacy of endothelin receptor antagonists against GBM. In this context, we have designed an immunoPET radioligand combining the chimeric antibody targeting ETA, chimeric-Rendomab A63 (xiRA63), with 89Zr isotope and evaluated the abilities of xiRA63 and its Fab (ThioFab-xiRA63) to detect ETA+ tumors in a mouse model xenografted orthotopically with patient-derived Gli7 GSCs. Results: Radioligands were intravenously injected and imaged over time by µPET-CT imaging. Tissue biodistribution and pharmacokinetic parameters were analyzed, highlighting the ability of [89Zr]Zr-xiRA63 to pass across the brain tumor barrier and achieve better tumor uptake than [89Zr]Zr-ThioFab-xiRA63. Conclusions: This study shows the high potential of [89Zr]Zr-xiRA63 in specifically targeting ETA+ tumors, thus raising the possibility of detecting and treating ETA+ GSCs, which could improve the management of GBM patients. [ABSTRACT FROM AUTHOR]

Purpose: Integrin αv is a key regulator in the pathophysiology of hepatic fibrosis. In this study, we evaluated the potential utility of an integrin αvβ3 positron emission tomography (PET) radiotracer, 18F-labeled cyclic arginine-glycine-aspartic acid penta-peptide ([18F]F-FPP-RGD2), for detecting hepatic integrin αv and function in nonalcoholic steatohepatitis (NASH) model rats using integrin αv siRNA. Methods: NASH model rats were produced by feeding a choline-deficient, low-methionine, high-fat diet for 8 weeks. PET/computerized tomography imaging and quantification of integrin αv protein, serum aspartate aminotransferase, and alanine aminotransferase were performed 1 week after single intravenous injection of integrin αv siRNA. Results: Integrin αv siRNA (0.1 and 0.5 mg/kg) dose-dependently decreased hepatic integrin αv protein concentrations in control and NASH model rats. The hepatic mean standard uptake value of [18F]F-FPP-RGD2 was decreased dose-dependently by integrin αv siRNA. The mean standard uptake value was positively correlated with integrin αv protein levels in control and NASH model rats. Serum aspartate aminotransferase and alanine aminotransferase concentrations were also decreased by siRNA injection and correlated with liver integrin αv protein expression levels in NASH model rats. Conclusion: This study suggests that [18F]F-FPP-RGD2 PET imaging is a promising radiotracer for monitoring hepatic integrin αv protein levels and hepatic function in NASH pathology. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) achieve a milestone in cancer treatment. Despite the great success of ICI, ICI therapy still faces a big challenge due to heterogeneity of tumor, and therapeutic response is complicated by possible immune-related adverse events (irAEs). Therefore, it is critical to assess the systemic immune response elicited by ICI therapy to guide subsequent treatment regimens. Positron emission tomography (PET) molecular imaging is an optimal approach in cancer diagnosis, treatment effect evaluation, follow-up, and prognosis prediction. PET imaging can monitor metabolic changes of immunocytes and specifically identify immuno-biomarkers to reflect systemic immune responses. Here, we briefly review the application of PET molecular imaging to date of systemic immune responses following ICI therapy and the associated rationale. [ABSTRACT FROM AUTHOR]

This review describes the basic principles of radiometal-theranostics and its dawn based on the development of the positron-emitting 86Y and 86Y-labeled radiopharmaceuticals to quantify biodistribution and dosimetry of 90Y-labeled analogue therapeutics. The nuclear and inorganic development of 86Y (including nuclear and cross section data, irradiation, radiochemical separation and recovery) led to preclinical and clinical evaluation of 86Y-labeled citrate and EDTMP complexes and yielded organ radiation doses in terms of mGy/MBq 90Y. The approach was extended to [86/90Y]Y-DOTA-TOC, yielding again yielded organ radiation doses in terms of mGy/MBq 90Y. The review further discusses the consequences of this early development in terms of further radiometals that were used (68Ga, 177Lu etc.), more chelators that were developed, new biological targets that were addressed (SSTR, PSMA, FAP, etc.) and subsequent generations of radiometal-theranostics that resulted out of that. [ABSTRACT FROM AUTHOR]

Background: The assessment of anomalous coronary arteries (AAOCA) remains controversial without an optimal stress modality for ischemia. We evaluated the value of PET-CT myocardial perfusion imaging in these patients and subsequent management. Methods and results: AAOCA patients (n = 82) undergoing PET-CT from 2015 to 2021 were retrospectively chart reviewed. Multivariable analyses performed to assess relevant clinical and imaging factors associated with ischemia on PET and AAOCA surgery. Key characteristics include mean age 45 ± 20 years, 30 (37%) female, 45 (55%) with chest pain, 19 (23%) anomalous left main coronary artery, 58 (71%) anomalous right coronary artery, 26 (32%) with objective ischemia on PET-CT, and 37 (45%) who underwent AAOCA surgery. Adverse outcomes over mean follow-up of 2.2 ± 1.8 years included one death and two myocardial infarctions. Anomalous left main was independently associated with ischemia on PET-CT, odds ratio (95% confidence intervals) 4.15 (1.31–13.1), P =.006. Chest pain and ischemia on PET-CT were independently associated with and provided incremental prognostic value for surgery, odds ratio 9.73 (2.78–34.0), P <.001 and 6.79 (1.99–23.2), P =.002, respectively. Conclusion: Ischemia on PET-CT occurred in a third of our cohort, identifying patients who may benefit from surgery. Larger studies are needed to evaluate the interplay between AAOCA, ischemia by PET and surgery. [ABSTRACT FROM AUTHOR]

Objectives: To develop a novel analytical approach based on 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) metabolic parameters, serum inflammatory markers, and clinical variables to improve the outcome prediction in NSCLC. Methods: A total of 190 newly diagnosed NSCLC patients who underwent pretreatment [18F]FDG PET/CT were retrospectively enrolled and divided into a training cohort (n = 127) and a test cohort (n = 63). Cox regression analysis was used to investigate the predictive values of PET metabolic parameters, inflammation markers, and clinical variables for progression-free survival (PFS) and overall survival (OS). Based on the results of multivariate analysis, PET-based, clinical, and combined models were constructed. The predictive performance of different models was evaluated using time-dependent ROC curve analysis, Harrell concordance index (C-index), calibration curve, and decision curve analysis. Results: The combined models incorporating SULmax, MTV, NLR, and ECOG PS demonstrated significant prognostic superiority over PET-based models, clinical models, and TNM stage in terms of both PFS (C-index: 0.813 vs. 0.786 vs. 0.776 vs. 0.678, respectively) and OS (C-index: 0.856 vs. 0.792 vs. 0.781 vs. 0.674, respectively) in the training cohort. Similar results were observed in the test cohort for PFS (C-index: 0.808 vs. 0.764 vs. 0.748 vs. 0.679, respectively) and OS (C-index: 0.836 vs. 0.785 vs. 0.726 vs. 0.660, respectively) prediction. The combined model calibrated well in two cohorts. Decision curve analysis supported the clinical utility of the combined model. Conclusions: We reported a novel analytical approach combining PET metabolic information with inflammatory biomarker and clinical characteristics, which could significantly improve outcome prediction in newly diagnosed NSCLC. Key Points: • The nomogram incorporating SULmax, MTV, NLR, and ECOG PS outperformed the TNM stage for outcome prediction in patients with newly diagnosed NSCLC. • The established nomogram could provide refined prognostic stratification. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common dementia worldwide. The exact etiology of AD is unclear as yet, and no effective treatments are currently available, making AD a tremendous burden posed on the whole society. As AD is a multifaceted and heterogeneous disease, and most biomarkers are dynamic in the course of AD, a range of biomarkers should be established to evaluate the severity and prognosis. Positron emission tomography (PET) offers a great opportunity to visualize AD from diverse perspectives by using radiolabeled agents involved in various pathophysiological processes; PET imaging technique helps to explore the pathomechanisms of AD comprehensively and find out the most appropriate biomarker in each AD phase, leading to a better evaluation of the disease. In this review, we discuss the application of PET in the course of AD and summarized radiolabeled compounds with favorable imaging characteristics. [ABSTRACT FROM AUTHOR]

Background: Myocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. 18F-flurpiridaz was recently introduced as a valid alternative to currently used PET-MPI probes. Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with 18F-flurpiridaz is feasible in mice. Methods: Rest/stress PET-MPI was performed with 18F-flurpiridaz (0.6-3.0 MBq) in 27 mice aged 7–8 months. Regadenoson (0.1 µg/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial 18F-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium. Results: Tracer kinetics were best described by a two-tissue compartment model. K1 ranged from 6.7 to 20.0 mL·cm−3·min−1, while myocardial volumes of distribution (VT) were between 34.6 and 83.6 mL·cm−3. Of note, myocardial 18F-flurpiridaz uptake (%ID/g) was significantly correlated with K1 at rest and following pharmacological vasodilation for all time intervals assessed. However, while Spearman's coefficients (rs) ranged between 0.478 and 0.681, R2 values were generally low. In contrast, an excellent correlation of myocardial 18F-flurpiridaz uptake with VT was obtained, particularly when employing the averaged myocardial uptake from 20 to 40 min post tracer injection (R2 ≥ 0.98). Notably, K1 and VT were similarly sensitive to pharmacological vasodilation induction. Further, mean stress-to-rest ratios of K1, VT, and %ID/g 18F-flurpiridaz were virtually identical, suggesting that %ID/g 18F-flurpiridaz can be used to estimate coronary flow reserve (CFR) in mice. Conclusion: Our findings suggest that a simplified assessment of relative myocardial perfusion and CFR, based on image-derived tracer uptake, is feasible with 18F-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) mapping for cerebral glucose metabolism in drug-sensitive and drug-resistant pediatric epilepsy patients.This retrospective study enrolled 40 patients and 25 controls. Patients were categorized into drug-sensitive epilepsy (n = 22) and drug-resistant epilepsy (n = 18) according to the seizure frequency at follow-up. All patients underwent two [18F]FDG PET scans separated by a minimum of one year. Absolute asymmetry index (|AI|) was calculated for assessing metabolic differences and changes in epileptic foci. Statistical Parametric Mapping (SPM) was utilized to reveal voxel-wise metabolic characteristics and alterations throughout the brain. Network analysis based on graph theory was used to investigate network-level differences between the two patient groups.The drug-sensitive group showed a lower |AI| at both baseline (P = 0.038) and follow-up (P = 0.003) PET scans than the drug-resistant group. |AI| decreased in the drug-sensitive group and increased in the drug-resistant group across scans, but these trends were not statistically significant (P = 0.240 and P = 0.450, respectively). Both groups exhibited hypometabolism at baseline. The drug-sensitive group showed less hypometabolic brain regions than the drug-resistant group. The drug-sensitive maintained stable level of hypometabolism between the two scans, whereas the drug-resistant group showed an increasing hypometabolism. Network analysis demonstrated that the drug-sensitive group had a higher global efficiency, average degree, and clustering, along with a shorter characteristic path length compared to the drug-resistant group.For the first time, this study revealed in vivo cerebral glucose metabolic pattern of nonsurgical pediatric epilepsy patients treated by antiepileptic drugs. Especially, drug-resistant epilepsy patients represented significantly extensive and progressive hypometabolism with inefficient brain network connectivity compared with drug-sensitive epilepsy. [18F]FDG PET imaging may be a potential visual approach for theranostics of epilepsy patients.Methods: This study aimed to investigate [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) mapping for cerebral glucose metabolism in drug-sensitive and drug-resistant pediatric epilepsy patients.This retrospective study enrolled 40 patients and 25 controls. Patients were categorized into drug-sensitive epilepsy (n = 22) and drug-resistant epilepsy (n = 18) according to the seizure frequency at follow-up. All patients underwent two [18F]FDG PET scans separated by a minimum of one year. Absolute asymmetry index (|AI|) was calculated for assessing metabolic differences and changes in epileptic foci. Statistical Parametric Mapping (SPM) was utilized to reveal voxel-wise metabolic characteristics and alterations throughout the brain. Network analysis based on graph theory was used to investigate network-level differences between the two patient groups.The drug-sensitive group showed a lower |AI| at both baseline (P = 0.038) and follow-up (P = 0.003) PET scans than the drug-resistant group. |AI| decreased in the drug-sensitive group and increased in the drug-resistant group across scans, but these trends were not statistically significant (P = 0.240 and P = 0.450, respectively). Both groups exhibited hypometabolism at baseline. The drug-sensitive group showed less hypometabolic brain regions than the drug-resistant group. The drug-sensitive maintained stable level of hypometabolism between the two scans, whereas the drug-resistant group showed an increasing hypometabolism. Network analysis demonstrated that the drug-sensitive group had a higher global efficiency, average degree, and clustering, along with a shorter characteristic path length compared to the drug-resistant group.For the first time, this study revealed in vivo cerebral glucose metabolic pattern of nonsurgical pediatric epilepsy patients treated by antiepileptic drugs. Especially, drug-resistant epilepsy patients represented significantly extensive and progressive hypometabolism with inefficient brain network connectivity compared with drug-sensitive epilepsy. [18F]FDG PET imaging may be a potential visual approach for theranostics of epilepsy patients.Results: This study aimed to investigate [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) mapping for cerebral glucose metabolism in drug-sensitive and drug-resistant pediatric epilepsy patients.This retrospective study enrolled 40 patients and 25 controls. Patients were categorized into drug-sensitive epilepsy (n = 22) and drug-resistant epilepsy (n = 18) according to the seizure frequency at follow-up. All patients underwent two [18F]FDG PET scans separated by a minimum of one year. Absolute asymmetry index (|AI|) was calculated for assessing metabolic differences and changes in epileptic foci. Statistical Parametric Mapping (SPM) was utilized to reveal voxel-wise metabolic characteristics and alterations throughout the brain. Network analysis based on graph theory was used to investigate network-level differences between the two patient groups.The drug-sensitive group showed a lower |AI| at both baseline (P = 0.038) and follow-up (P = 0.003) PET scans than the drug-resistant group. |AI| decreased in the drug-sensitive group and increased in the drug-resistant group across scans, but these trends were not statistically significant (P = 0.240 and P = 0.450, respectively). Both groups exhibited hypometabolism at baseline. The drug-sensitive group showed less hypometabolic brain regions than the drug-resistant group. The drug-sensitive maintained stable level of hypometabolism between the two scans, whereas the drug-resistant group showed an increasing hypometabolism. Network analysis demonstrated that the drug-sensitive group had a higher global efficiency, average degree, and clustering, along with a shorter characteristic path length compared to the drug-resistant group.For the first time, this study revealed in vivo cerebral glucose metabolic pattern of nonsurgical pediatric epilepsy patients treated by antiepileptic drugs. Especially, drug-resistant epilepsy patients represented significantly extensive and progressive hypometabolism with inefficient brain network connectivity compared with drug-sensitive epilepsy. [18F]FDG PET imaging may be a potential visual approach for theranostics of epilepsy patients.Conclusions: This study aimed to investigate [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) mapping for cerebral glucose metabolism in drug-sensitive and drug-resistant pediatric epilepsy patients.This retrospective study enrolled 40 patients and 25 controls. Patients were categorized into drug-sensitive epilepsy (n = 22) and drug-resistant epilepsy (n = 18) according to the seizure frequency at follow-up. All patients underwent two [18F]FDG PET scans separated by a minimum of one year. Absolute asymmetry index (|AI|) was calculated for assessing metabolic differences and changes in epileptic foci. Statistical Parametric Mapping (SPM) was utilized to reveal voxel-wise metabolic characteristics and alterations throughout the brain. Network analysis based on graph theory was used to investigate network-level differences between the two patient groups.The drug-sensitive group showed a lower |AI| at both baseline (P = 0.038) and follow-up (P = 0.003) PET scans than the drug-resistant group. |AI| decreased in the drug-sensitive group and increased in the drug-resistant group across scans, but these trends were not statistically significant (P = 0.240 and P = 0.450, respectively). Both groups exhibited hypometabolism at baseline. The drug-sensitive group showed less hypometabolic brain regions than the drug-resistant group. The drug-sensitive maintained stable level of hypometabolism between the two scans, whereas the drug-resistant group showed an increasing hypometabolism. Network analysis demonstrated that the drug-sensitive group had a higher global efficiency, average degree, and clustering, along with a shorter characteristic path length compared to the drug-resistant group.For the first time, this study revealed in vivo cerebral glucose metabolic pattern of nonsurgical pediatric epilepsy patients treated by antiepileptic drugs. Especially, drug-resistant epilepsy patients represented significantly extensive and progressive hypometabolism with inefficient brain network connectivity compared with drug-sensitive epilepsy. [18F]FDG PET imaging may be a potential visual approach for theranostics of epilepsy patients. [ABSTRACT FROM AUTHOR]

Purpose: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM.Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential.The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430.Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.Experimental design: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM.Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential.The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430.Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.Results: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM.Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential.The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430.Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.Conclusions: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM.Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential.The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430.Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy. [ABSTRACT FROM AUTHOR]

Purpose: Integrins αv are key molecules in the pathogenesis of fibrosis in multiple organs. To assess the potential utility of integrin αvβ3 imaging for idiopathic pulmonary fibrosis (IPF), we evaluated an 18F-FPP-RGD2 PET probe in a rat model of bleomycin-induced lung fibrosis. Methods: Pulmonary fibrosis was induced by single intratracheal instillation of bleomycin (3 mg/rat). Positron emission tomography (PET)/computerized tomography scans were performed 4 weeks after bleomycin administration using 18F-FPP-RGD2. Total distribution volume (VT) was estimated using one-tissue/two-compartment, two-tissue/three-compartment models, and Logan graphical analysis (Logan plot; t* = 30 min). Plasma-free fractions were estimated from images of the left ventricle. Correlation between Logan VT and lung pathology was assessed by Spearman's rank correlation. Results: Histopathological evaluation demonstrated the development of fibrosis in IPF-model group. Integrin αv protein expression and lung radioactivity were higher in IPF-model group compared with control group. The lung radioactivity of 18F-FPP-RGD2 rapidly reached the peak after administration and then gradually decreased, whereas left ventricular radioactivity rapidly disappeared. Logan graphical analysis was found to be suitable for 18F-FPP-RGD2 kinetic analysis in the IPF-model lung. Logan VT values for 18F-FPP-RGD2 were significantly higher in IPF rats compared with control rats and strongly correlated with lung fibrosis, pathology, integrin αv protein expression, and oxygen partial pressure. Conclusion: Our findings demonstrate that the integrin αvβ3 PET probe 18F-FPP-RGD2 can detect pathophysiological changes in lungs, including fibrosis accompanying upregulated integrin αv of IPF-model rats. These findings support the utility of 18F-FPP-RGD2 PET imaging for the pathophysiological evaluation of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Purpose of Review: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently defined neurodegenerative disease characterized by amnestic phenotype and pathological inclusions of TAR DNA-binding protein 43 (TDP-43). LATE is distinct from rarer forms of TDP-43 diseases such as frontotemporal lobar degeneration with TDP-43 but is also a common copathology with Alzheimer's disease (AD) and cerebrovascular disease and accelerates cognitive decline. LATE contributes to clinicopathologic heterogeneity in neurodegenerative diseases, so it is imperative to distinguish LATE from other etiologies. Recent Findings: Novel biomarkers for LATE are being developed with magnetic resonance imaging (MRI) and positron emission tomography (PET). When cooccurring with AD, LATE exhibits identifiable patterns of limbic-predominant atrophy on MRI and hypometabolism on 18F-fluorodeoxyglucose PET that are greater than expected relative to levels of local AD pathology. Efforts are being made to develop TDP-43-specific radiotracers, molecularly specific biofluid measures, and genomic predictors of TDP-43. LATE is a highly prevalent neurodegenerative disease distinct from previously characterized cognitive disorders. [ABSTRACT FROM AUTHOR]

Objective: Hepatocellular carcinoma (HCC) is a malignant tumor associated with high morbidity and mortality rates. In many non-prostate solid tumors such as HCC, prostate-specific membrane antigens (PSMA) are overexpressed in tumor-associated endothelial cells. Therefore, the aim of this study was to evaluate the performance of [68Ga]Ga-PSMA-617 PET imaging on HCC with different animal models, including cell line-derived xenografts (CDX) and patient-derived xenografts (PDX), and to explore its mechanisms of function. Methods: [68Ga]Ga-PSMA-617 was prepared. The expression level of PSMA in two human hepatocellular cancer cells (HepG2 and HuH-7) was evaluated, and the cellular uptakes of [68Ga]Ga-PSMA-617 were assayed. HepG2 and HuH-7 subcutaneous xenograft models, HepG2 orthotopic xenograft models, and four different groups of PDX models were prepared. Preclinical pharmacokinetics and performance of [68Ga]Ga-PSMA-617 were evaluated in different types of HCC xenografts models using small animal PET and biodistribution studies. Results: Low PSMA expression level of HepG2 and HuH-7 cells was observed, and the cellular uptake and blocking study confirmed the non-specificity of the PSMA-targeted probe binding to HepG2 and HuH-7 cells. In the subcutaneous xenograft models, the tumor uptakes at 0.5 h were 0.76 ± 0.12%ID/g (HepG2 tumors) and 0.78 ± 0.08%ID/g (HuH-7 tumors), respectively, which were significantly higher than those of the blocking groups (0.23 ± 0.04%ID/g and 0.20 ± 0.04%ID/g, respectively). In the orthotopic xenograft models, PET images clearly displayed the tumor locations based on the preferential accumulation of [68Ga]Ga-PSMA-617 in tumor tissue versus normal liver tissue, suggesting the possibility of using [68Ga]Ga-PSMA-617 PET imaging to detect primary HCC lesions in deep tissue. In the four different groups of HCC PDX models, PET imaging with [68Ga]Ga-PSMA-617 provided clear tumor uptakes with prominent tumor-to-background contrast, further demonstrating its potential for the clinical imaging of PSMA-positive HCC lesions. The staining of tumor tissue sections with CD31- and PSMA-specific antibodies visualized the tumor-associated blood vessels and PSMA expression on endothelial cells in subcutaneous, orthotopic tissues, and PDX tissues, confirming the imaging with [68Ga]Ga-PSMA-617 might be mediated by targeting tumor associated endothelium. Conclusion: In this study, in vivo PET on different types of HCC xenograft models illustrated high uptake within tumors, which confirmed that [68Ga]Ga-PSMA-617 PET may be a promising imaging modality for HCC by targeting tumor associated endothelium. [ABSTRACT FROM AUTHOR]

Automated amyloid-PET image classification can support clinical assessment and increase diagnostic confidence. Three automated approaches using global cut-points derived from Receiver Operating Characteristic (ROC) analysis, machine learning (ML) algorithms with regional SUVr values, and deep learning (DL) network with 3D image input were compared under various conditions: number of training data, radiotracers, and cohorts. 276 [11C]PiB and 209 [18F]AV45 PET images from ADNI database and our local cohort were used. Global mean and maximum SUVr cut-points were derived using ROC analysis. 68 ML models were built using regional SUVr values and one DL network was trained with classifications of two visual assessments – manufacturer's recommendations (gray-scale) and with visually guided reference region scaling (rainbow-scale). ML-based classification achieved similarly high accuracy as ROC classification, but had better convergence between training and unseen data, with a smaller number of training data. Naïve Bayes performed the best overall among the 68 ML algorithms. Classification with maximum SUVr cut-points yielded higher accuracy than with mean SUVr cut-points, particularly for cohorts showing more focal uptake. DL networks can support the classification of definite cases accurately but performed poorly for equivocal cases. Rainbow-scale standardized image intensity scaling and improved inter-rater agreement. Gray-scale detects focal accumulation better, thus classifying more amyloid-positive scans. All three approaches generally achieved higher accuracy when trained with rainbow-scale classification. ML yielded similarly high accuracy as ROC, but with better convergence between training and unseen data, and further work may lead to even more accurate ML methods. [ABSTRACT FROM AUTHOR]

Background: CD4+ T cells are central inflammatory mediators in the pathogenesis of autoimmune rheumatoid arthritis (RA), as they are one of the dominating cell types in synovial inflammation. Molecular imaging of CD4+ T cells has potential role for early detection and monitoring of RA. Here, we developed a new radiotracer for in vivo immunoPET imaging of murine CD4+ T cells and tested it in the collagen-induced arthritis (CIA) mouse model of human RA. Results: The tracer, [64Cu]Cu-NOTA-CD4-F(ab)'2 ([64Cu]Cu-NOTA-CD4), was generated from F(ab)'2 fragments of R-anti-mouse CD4 antibodies conjugated to the 2-S-(isothiocyanatbenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) chelator and radiolabeled with copper-64. Accumulation of the tracer and isotype control was evaluated in the CIA model and mice receiving whole-body irradiation (WBI) (5 Gy). The potential of [64Cu]Cu-NOTA-CD4 for response assessment was evaluated in CIA induced mice treated with dexamethasone (DXM). Imaging data were compared with flow cytometry and immunohistochemistry (IHC) of inflammatory cells including CD4+ T cells. [64Cu]Cu-NOTA-CD4 showed increased accumulation in T cell-rich tissues compared with isotype control (p < 0.0001). In addition, reduced accumulation of [64Cu]Cu-NOTA-CD4 was observed in T cell-depleted tissue (p < 0.0001). Flow cytometry and IHC confirmed the increased infiltration of CD4+ T cells in CIA mice. Conclusions: We developed and evaluated a new radiotracer, [64Cu]Cu-NOTA-CD4, for immunoPET imaging of murine CD4+ T cells. [64Cu]Cu-NOTA-CD4 was successfully synthesized by F(ab)'2 fragments of R-anti-mouse CD4 antibodies conjugated to a chelator and radiolabeled with copper-64. We found that our novel CD4 PET tracer can be used for noninvasive visualization of murine CD4+ T cells. [ABSTRACT FROM AUTHOR]

Quantification approaches of positron emission tomography (PET) imaging provide user-independent evaluation of pathophysiological processes in living brains, which have been strongly recommended in clinical diagnosis of neurological disorders. Most PET quantification approaches depend on spatial normalization of PET images to brain template; however, the spatial normalization and quantification approaches have not been comprehensively reviewed. In this review, we introduced and compared PET template-based and magnetic resonance imaging (MRI)-aided spatial normalization approaches. Tracer-specific and age-specific PET brain templates were surveyed between 1999 and 2021 for 18F-FDG, 11C-PIB, 18F-Florbetapir, 18F-THK5317, and etc., as well as adaptive PET template methods. Spatial normalization-based PET quantification approaches were reviewed, including region-of-interest (ROI)-based and voxel-wise quantitative methods. Spatial normalization-based ROI segmentation approaches were introduced, including manual delineation on template, atlas-based segmentation, and multi-atlas approach. Voxel-wise quantification approaches were reviewed, including voxel-wise statistics and principal component analysis. Certain concerns and representative examples of clinical applications were provided for both ROI-based and voxel-wise quantification approaches. At last, a recipe for PET spatial normalization and quantification approaches was concluded to improve diagnosis accuracy of neurological disorders in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: End-of-life studies have validated the binary visual reads of 18F-labeled amyloid PET tracers as an accurate tool for the presence or absence of increased neuritic amyloid plaque density. In this study, the performance of a support vector machine (SVM)-based classifier will be tested against pathological ground truths and its performance determined in cognitively healthy older adults. Methods: We applied SVM with a linear kernel to an 18F-Flutemetamol end-of-life dataset to determine the regions with the highest feature weights in a data-driven manner and to compare between two different pathological ground truths: based on neuritic amyloid plaque density or on amyloid phases, respectively. We also trained and tested classifiers based on the 10% voxels with the highest amplitudes of feature weights for each of the two neuropathological ground truths. Next, we tested the classifiers' diagnostic performance in the asymptomatic Alzheimer's disease (AD) phase, a phase of interest for future drug development, in an independent dataset of cognitively intact older adults, the Flemish Prevent AD Cohort-KU Leuven (F-PACK). A regression analysis was conducted between the Centiloid (CL) value in a composite volume of interest (VOI), as index for amyloid load, and the distance to the hyperplane for each of the two classifiers, based on the two pathological ground truths. A receiver operating characteristic analysis was also performed to determine the CL threshold that optimally discriminates between neuritic amyloid plaque positivity versus negativity, or amyloid phase positivity versus negativity, within F-PACK. Results: The classifiers yielded adequate specificity and sensitivity within the end-of-life dataset (neuritic amyloid plaque density classifier: specificity of 90.2% and sensitivity of 83.7%; amyloid phase classifier: specificity of 98.4% and sensitivity of 84.0%). The regions with the highest feature weights corresponded to precuneus, caudate, anteromedial prefrontal, and also posterior inferior temporal and inferior parietal cortex. In the cognitively normal cohort, the correlation coefficient between CL and distance to the hyperplane was −0.66 for the classifier trained with neuritic amyloid plaque density, and −0.88 for the classifier trained with amyloid phases. This difference was significant. The optimal CL cut-off for discriminating positive versus negative scans was CL = 48–51 for the different classifiers (area under the curve (AUC) = 99.9%), except for the classifier trained with amyloid phases and based on the 10% voxels with highest feature weights. There the cut-off was CL = 26 (AUC = 99.5%), which closely matched the CL threshold for discriminating phases 0–2 from 3–5 based on the end-of-life dataset and the neuropathological ground truth. Discussion: Among a set of neuropathologically validated classifiers trained with end-of-life cases, transfer to a cognitively normal population works best for a classifier trained with amyloid phases and using only voxels with the highest amplitudes of feature weights. [ABSTRACT FROM AUTHOR]

Microcalcification, a type of vascular calcification, increases the instability of plaque and easily leads to acute clinical events. Positron emission tomography (PET) is a new examination technology with significant advantages in identifying vascular calcification, especially microcalcification. The use of the 18F-NaF is undoubtedly the benchmark, and other PET tracers related to vascular calcification are also currently in development. Despite all this, a large number of studies are still needed to further clarify the specific mechanisms and characteristics. This review aimed at providing a summary of the application and progress of different PET tracers and also the future development direction. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of migraine is mainly clinical and self-reported, which makes additional examinations unnecessary in most cases. Migraine can be subtyped into chronic (CM) and episodic (EM). Despite the very high prevalence of migraine, there are no evidence-based guidelines for differentiating between these subtypes other than the number of days of migraine headache per month. Thus, we consider it timely to perform a systematic review to search for physiological evidence from functional activity (as opposed to anatomical structure) for the differentiation between CM and EM, as well as potential functional biomarkers. For this purpose, Web of Science (WoS), Scopus, and PubMed databases were screened. Findings: Among the 24 studies included in this review, most of them (22) reported statistically significant differences between the groups of CM and EM. This finding is consistent regardless of brain activity acquisition modality, ictal stage, and recording condition for a wide variety of analyses. That speaks for a supramodal and domain-general differences between CM and EM that goes beyond a differentiation based on the days of migraine per month. Together, the reviewed studies demonstrates that electro- and magneto-physiological brain activity (M/EEG), as well as neurovascular and metabolic recordings from functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), show characteristic patterns that allow to differentiate between CM and EM groups. Conclusions: Although a clear brain activity-based biomarker has not yet been identified to distinguish these subtypes of migraine, research is approaching headache specialists to a migraine diagnosis based not only on symptoms and signs reported by patients. Future studies based on M/EEG should pay special attention to the brain activity in medium and fast frequency bands, mainly the beta band. On the other hand, fMRI and PET studies should focus on neural circuits and regions related to pain and emotional processing. [ABSTRACT FROM AUTHOR]

Purpose: Recent studies have linked activated spinal glia to neuropathic pain. Here, using a positron emission tomography (PET) scanner with high spatial resolution and sensitivity, we evaluated the feasibility and sensitivity of N,N-diethyl-2-(2-(4-([18F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide ([18F]F-DPA) imaging for detecting spinal cord microglial activation after partial sciatic nerve ligation (PSNL) in rats.Procedures: Neuropathic pain was induced in rats (n = 20) by PSNL, and pain sensation tests were conducted before surgery and 3 and 7 days post-injury. On day 7, in vivo PET imaging and ex vivo autoradiography were performed using [18F]F-DPA or [11C]PK11195. Ex vivo biodistribution and PET imaging of the removed spinal cord were carried out with [18F]F-DPA. Sham-operated and PK11195-pretreated animals were also examined.Results: Mechanical allodynia was confirmed in the PSNL rats from day 3 through day 7. Ex vivo autoradiography showed a higher lesion-to-background uptake with [18F]F-DPA compared with [11C]PK11195. Ex vivo PET imaging of the removed spinal cord showed [18F]F-DPA accumulation in the inflammation site, which was immunohistochemically confirmed to coincide with microglia activation. Pretreatment with PK11195 eliminated the uptake. The SUV values of in vivo [18F]F-DPA and [11C]PK11195 PET were not significantly increased in the lesion compared with the reference region, and were fivefold higher than the values obtained from the ex vivo data. Ex vivo biodistribution revealed a twofold higher [18F]F-DPA uptake in the vertebral body compared to that seen in the bone from the skull.Conclusions: [18F]F-DPA aided visualization of the spinal cord inflammation site in PSNL rats on ex vivo autoradiography and was superior to [11C]PK11195. In vivo [18F]F-DPA PET did not allow for visualization of tracer accumulation even using a high-spatial-resolution PET scanner. The main reason for this result was due to insufficient SUVs in the spinal cord region as compared with the background noise, in addition to a spillover from the vertebral body. [ABSTRACT FROM AUTHOR]

Radiomic analysis provides information on the underlying tumour heterogeneity in lymphoma, reflecting the real-time evolution of malignancy. 2-Deoxy-2-[18F] fluoro-D-glucose positron emission tomography ([18F] FDG PET/CT) imaging is recommended before, during, and at the end of treatment for almost all lymphoma patients. This methodology offers high specificity and sensitivity, which can aid in accurate staging and assist in prompt treatment. Pretreatment [18F] FDG PET/CT-based radiomics facilitates improved diagnostic ability, guides individual treatment regimens, and boosts outcome prognosis based on heterogeneity as well as the biological, pathological, and metabolic status of the lymphoma. This technique has attracted considerable attention given its numerous applications in medicine. In the current review, we will briefly describe the basic radiomics workflow and types of radiomic features. Details of current applications of baseline [18F] FDG PET/CT-based radiomics in lymphoma will be discussed, such as differential diagnosis from other primary malignancies, diagnosis of bone marrow involvement, and response and prognostic prediction. We will also describe how this technique provides a unique noninvasive platform to assess tumour heterogeneity. Newly emerging PET radiotracers and multimodality technology will improve diagnostic specificity and further clarify tumor biology and even genetic variations in lymphoma, potentially promoting the development of precision medicine. [ABSTRACT FROM AUTHOR]

Purpose: Epilepsy with centrotemporal spikes (ECTS) is the most common epilepsy syndrome in children and usually presents with cognitive dysfunctions. However, little is known about the processing speed dysfunction and the associated neuroimaging mechanism in ECTS. This study aims to investigate the brain functional abnormality of processing speed dysfunction in ECTS patients by using the 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI). Methods: This prospective study recruited twenty-eight ECTS patients who underwent the 18F-FDG PET, rs-fMRI, and neuropsychological examinations. Twenty children with extracranial tumors were included as PET controls, and 20 healthy children were recruited as MRI controls. The PET image analysis investigated glucose metabolism by determining standardized uptake value ratio (SUVR). The MRI image analysis explored abnormal functional connectivity (FC) within the cortical–striatal circuit through network-based statistical (NBS) analysis. Correlation analysis was performed to explore the relationship between SUVR, FC, and processing speed index (PSI). Results: Compared with healthy controls, ECTS patients showed normal intelligence quotient but significantly decreased PSI (P = 0.04). PET analysis showed significantly decreased SUVRs within bilateral caudate, putamen, pallidum, left NAc, right rostral middle frontal gyrus, and frontal pole of ECTS patients (P < 0.05). Rs-fMRI analysis showed absolute values of 20 FCs were significantly decreased in ECTS patients compared with MRI controls, which connected 16 distinct ROIs. The average SUVR of right caudate and the average of 20 FCs were positively correlated with PSI in ECTS patients (P = 0.034 and P = 0.005, respectively). Conclusion: This study indicated that ECTS patients presented significantly reduced PSI, which is closely associated with decreased SUVR and FC of cortical–striatal circuit. Caudate played an important role in processing speed dysfunction. Clinical trial registration: NCT04954729; registered on July 8, 2021, public site, https://clinicaltrials.gov/ct2/show/NCT04954729 [ABSTRACT FROM AUTHOR]

Purpose: Alzheimer's disease (AD) studies revealed that abnormal deposition of tau spreads in a specific spatial pattern, namely Braak stage. However, Braak staging is based on post mortem brains, each of which represents the cross section of the tau trajectory in disease progression, and numerous studies were reported that do not conform to that model. This study thus aimed to identify the tau trajectory and quantify the tau progression in a data-driven approach with the continuous latent space learned by variational autoencoder (VAE). Methods: A total of 1080 [18F]Flortaucipir brain positron emission tomography (PET) images were collected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. VAE was built to compress the hidden features from tau images in latent space. Hierarchical agglomerative clustering and minimum spanning tree (MST) were applied to organize the features and calibrate them to the tau progression, thus deriving pseudo-time. The image-level tau trajectory was inferred by continuously sampling across the calibrated latent features. We assessed the pseudo-time with regard to tau standardized uptake value ratio (SUVr) in AD-vulnerable regions, amyloid deposit, glucose metabolism, cognitive scores, and clinical diagnosis. Results: We identified four clusters that plausibly capture certain stages of AD and organized the clusters in the latent space. The inferred tau trajectory agreed with the Braak staging. According to the derived pseudo-time, tau first deposits in the parahippocampal and amygdala, and then spreads to the fusiform, inferior temporal lobe, and posterior cingulate. Prior to the regional tau deposition, amyloid accumulates first. Conclusion: The spatiotemporal trajectory of tau progression inferred in this study was consistent with Braak staging. The profile of other biomarkers in disease progression agreed well with previous findings. We addressed that this approach additionally has the potential to quantify tau progression as a continuous variable by taking a whole-brain tau image into account. [ABSTRACT FROM AUTHOR]

In recent years, silicon photomultiplier (SiPM) is replacing the photomultiplier tube (PMT) in positron emission tomography (PET) systems due to its superior properties, such as fast single-photon timing response, small gap between adjacent photosensitive pixels in the array, and insensitivity to magnetic fields. One of the technical challenges when developing SiPM-based PET systems or other position-sensitive radiation detectors is the large number of output channels coming from the SiPM array. Therefore, various signal multiplexing methods have been proposed to reduce the number of output channels and the load on the subsequent data acquisition (DAQ) system. However, the large PN-junction capacitance and quenching resistance of the SiPM yield undesirable resistance–capacitance delay when multiple SiPMs are combined, which subsequently causes the accumulation of dark counts and signal fluctuation of SiPMs. Therefore, without proper SiPM signal handling and processing, the SiPMs may yield worse timing characteristics than the PMTs. This article reviews the evolution of signal readout and multiplexing methods for the SiPM. In this review, we focus primarily on analog electronics for SiPM signal multiplexing, which allows for the reduction of DAQ channels required for the SiPM-based position-sensitive detectors used in PET and other radiation detector systems. Although the applications of most technologies described in the article are not limited to PET systems, the review highlights efforts to improve the physical performance (e.g. spatial, energy, and timing resolutions) of PET detectors and systems. [ABSTRACT FROM AUTHOR]