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Positron emission tomography/computed tomography (PET/CT) with 18F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden in systemic light-chain (AL) amyloidosis. However, its prognostic value is not known. The authors' aim was to evaluate the prognostic value of LV amyloid burden quantified by 18F-florbetapir PET/CT, and to identify mechanistic pathways mediating its association with outcomes. A total of 81 participants with newly diagnosed AL amyloidosis underwent 18F-florbetapir PET/CT imaging. Amyloid burden was quantified using 18F-florbetapir LV uptake as percent injected dose. The Mayo stage for AL amyloidosis was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and free light chain levels. Major adverse cardiac events (MACE) were defined as all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months. Among participants (median age, 61 years; 57% males), 36% experienced MACE, increasing from 7% to 63% across tertiles of LV amyloid burden (P < 0.001). LV amyloid burden was associated with MACE (HR: 1.46; 95% CI: 1.16-1.83; P = 0.001). However, this association became nonsignificant when adjusted for Mayo stage. In mediation analysis, the association between LV amyloid burden and MACE was mediated by NT-proBNP (P < 0.001), a marker of cardiomyocyte stretch and heart failure, and a component of Mayo stage. In this first study to link cardiac 18F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by percent injected dose predicted MACE in AL amyloidosis. This effect was not independent of Mayo stage and was mediated primarily through NT-proBNP. These findings provide novel insights into the mechanism linking myocardial amyloid deposits to MACE. [Display omitted] [ABSTRACT FROM AUTHOR]

Positron Emission Tomography (PET) image reconstruction remains a pivotal area in PET technology, critically influencing clinical diagnostic outcomes. Addressing the need for enhanced image quality, this study introduces a novel algorithm for PET image reconstruction. This algorithm integrates a penalty mechanism, morphological filtering, and the Maximum Likelihood Expectation Maximization (MLEM) algorithm, aiming to improve reconstructed image quality significantly. The operational process of the algorithm within each iteration encompasses two primary phases. Initially, image reconstruction is accomplished via the MLEM algorithm, followed by the application of a morphological filter to attenuate noise in the reconstructed image. Simulation experiments demonstrate that this algorithm effectively mitigates noise while preserving crucial details, such as image edges. Notably, this method presents the dual benefits of straightforward parameter configuration and ease of implementation. The results indicate a substantial enhancement in noise suppression and fine structure preservation in the reconstructed images, marking a significant advancement in PET image reconstruction techniques. [ABSTRACT FROM AUTHOR]

• Metabolic PET radiomics features were strong predictors of seizure recurrence. • PET-based radiomics score, SGS, and Durmon were significant predictors of seizure-free outcomes. • A nomogram incorporating PET-based radiomics and clinical risk factors demonstrated good performance in predicting surgery outcomes. To establish and validate a novel nomogram based on clinical characteristics and [18F]FDG PET radiomics for the prediction of postsurgical seizure freedom in patients with temporal lobe epilepsy (TLE). 234 patients with drug-refractory TLE patients were included with a median follow-up time of 24 months after surgery. The correlation coefficient redundancy analysis and LASSO Cox regression were used to characterize risk factors. The Cox model was conducted to develop a Clinic-PET nomogram to predict the relapse status in the training set (n = 171). The nomogram's performance was estimated through discrimination, calibration, and clinical utility. The prognostic prediction model was validated in the test set (n = 63). Eight radiomics features were selected to assess the radiomics score (radscore) of the operation side (Lat_radscore) and the asymmetric index (AI) of the radiomics score (AI_radscore). AI_radscor, Lat_radscor, secondarily generalized seizures (SGS), and duration between seizure onset and surgery (Durmon) were significant predictors of seizure-free outcomes. The final model had a C-index of 0.68 (95 %CI: 0.59–0.77) for complete freedom from seizures and time-dependent AUROC was 0.65 at 12 months, 0.65 at 36 months, and 0.59 at 60 months in the test set. A web application derived from the primary predictive model was displayed for economic and efficient use. A PET-based radiomics nomogram is clinically promising for predicting seizure outcomes after temporal lobe epilepsy surgery. [ABSTRACT FROM AUTHOR]

Accurate detection of focal cortical dysplasia (FCD) through magnetic resonance imaging (MRI) plays a pivotal role in the preoperative assessment of epilepsy. The integration of multimodal imaging has demonstrated substantial value in both diagnosing FCD and devising effective surgical strategies. This study aimed to enhance MRI post-processing by incorporating positron emission tomography (PET) analysis. We sought to compare the diagnostic efficacy of diverse image post-processing methodologies in patients presenting MRI-negative FCD. In this retrospective investigation, we assembled a cohort of patients with negative preoperative MRI results. T1-weighted volumetric sequences were subjected to morphometric analysis program (MAP) and composite parametric map (CPM) post-processing techniques. We independently co-registered images derived from various methods with PET scans. The alignment was subsequently evaluated, and its correlation was correlated with postoperative seizure outcomes. A total of 41 patients were enrolled in the study. In the PET-MAP(p = 0.0189) and PET-CPM(p = 0.00041) groups, compared with the non-overlap group, the overlap group significantly associated with better postoperative outcomes. In PET(p = 0.234), CPM(p = 0.686) and MAP(p = 0.672), there is no statistical significance between overlap and seizure-free outcomes. The sensitivity of using the CPM alone outperformed the MAP (0.65 vs 0.46). The use of PET-CPM demonstrated superior sensitivity (0.96), positive predictive value (0.83), and negative predictive value (0.91), whereas the MAP displayed superior specificity (0.71). Our findings suggested a superiority in sensitivity of CPM in detecting potential FCD lesions compared to MAP, especially when it is used in combination with PET for diagnosis of MRI-negative epilepsy patients. Moreover, we confirmed the superiority of synergizing metabolic imaging (PET) with quantitative maps derived from structural imaging (MAP or CPM) to enhance the identification of subtle epileptogenic zones (EZs). This study serves to illuminate the potential of integrated multimodal techniques in advancing our capability to pinpoint elusive pathological features in epilepsy cases. [ABSTRACT FROM AUTHOR]

Amyloid staging models showed that regional abnormality occurs before global positivity. Several studies assumed that the trajectory of amyloid spread is homogeneous, but clinical evidence suggests that it is highly heterogeneous. We tested whether different amyloid-β (Aβ) patterns exist by applying clustering on negative scans and investigating their demographics, clinical, cognitive, and biomarkers correlates, and cognitive trajectories. 151 individuals from Geneva and Zurich cohorts with T1-MRI, negative Aβ positron emission tomography (PET,centiloid<12) and clinical assessment were included. N = 123 underwent tau PET, and N = 65 follow-up neuropsychological assessment. We performed k-means clustering using 33 Aβ regional Standardized Uptake Vales ratio. Demographics, clinical, cognitive, and biomarkers differences were investigated. Longitudinal cognitive changes by baseline cluster status were estimated using a linear mixed model. The cluster analysis identified two clusters: temporal predominant (TP) and cingulate predominant (CP). TP tau deposition was higher than CP. A trend for a higher cognitive decline in TP compared to CP was observed. This study suggests the existence of two Aβ deposition patterns in the earliest phases of Aβ accumulation, differently prone to tau pathology and cognitive decline. [ABSTRACT FROM AUTHOR]

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• cCHP nanogel is a safe vaccine delivery system for nasally administered compounds. • Radiolabeled cCHP-nanogel was used in traditional biodistribution assays of mice. • We used a new PET method to assess the biodistribution of cCHP-nanogel in macaques. • In both animals, the CNS was free of nasally administered cCHP-nanogel. • Assessing the biodistribution of both vaccines and delivery systems is important. Cationic cholesteryl-group–bearing pullulan nanogel (cCHP-nanogel) is an effective drug-delivery system for nasal vaccines. However, cCHP-nanogel-based nasal vaccines might access the central nervous system due to its close proximity via the olfactory bulb in the nasal cavity. Using real-time quantitative tracking of the nanogel-based nasal botulinum neurotoxin and pneumococcal vaccines, we previously confirmed the lack of deposition of vaccine antigen in the cerebrum or olfactory bulbs of mice and non-human primates (NHPs), rhesus macaques. Here, we used positron emission tomography to investigate the biodistribution of the drug-delivery system itself, cCHP-nanogel after mice and NHPs were nasally administered with 18F-labeled cCHP nanogel. The results generated by the PET analysis of rhesus macaques were consistent with the direct counting of radioactivity due to 18F or 111In in dissected mouse tissues. Thus, no depositions of cCHP-nanogel were noted in the cerebrum, olfactory bulbs, or eyes of both species after nasal administration of the radiolabeled cCHP-nanogel compound. Our findings confirm the safe biodistribution of the cCHP-nanogel-based nasal vaccine delivery system in mice and NHPs. [ABSTRACT FROM AUTHOR]

The classification of prostate cancer (PCa) lesions using Prostate Imaging Reporting and Data System (PI-RADS) suffers from poor inter-reader agreement. This study compared quantitative parameters or radiomic features from multiparametric magnetic resonance imaging (mpMRI) or positron emission tomography (PET), as inputs into machine learning (ML) to predict the Gleason scores (GS) of detected lesions for improved PCa lesion classification. 20 biopsy-confirmed PCa subjects underwent imaging before radical prostatectomy. A pathologist assigned GS from tumour tissue. Two radiologists and one nuclear medicine physician delineated the lesions on the mpMR and PET images, yielding 45 lesion inputs. Seven quantitative parameters were extracted from the lesions, namely T2-weighted (T2w) image intensity, apparent diffusion coefficient (ADC), transfer constant (KTRANS), efflux rate constant (K ep), and extracellular volume ratio (V e) from mpMR images, and SUV mean and SUV max from PET images. Eight radiomic features were selected out of 109 radiomic features from T2w, ADC and PET images. Quantitative parameters or radiomic features, with risk factors of age, prostate-specific antigen (PSA), PSA density and volume, of 45 different lesion inputs were input in different combinations into four ML models - Decision Tree (DT), Support Vector Machine (SVM), k-Nearest-Neighbour (kNN), Ensembles model (EM). SUV max yielded the highest accuracy in discriminating detected lesions. Among the 4 ML models, kNN yielded the highest accuracies of 0.929 using either quantitative parameters or radiomic features with risk factors as input. ML models' performance is dependent on the input combinations and risk factors further improve ML classification accuracy. [Display omitted] • Among 7 quantitative parameters, SUV max correlated best with Gleason score (GS). • Machine learning yielded higher accuracies than using cut-points of parameters. • Quantitative parameters (QP) and radiomic features (RF) as inputs for GS prediction. • K-Nearest Neighbour yielded highest accuracy of 0.929 with QP and RF. • Combinations of parameters, risk factors and models affect classification accuracy. [ABSTRACT FROM AUTHOR]

(S)-ketamine is an NMDA receptor antagonist, but it also binds to and activates mu opioid receptors (MORs) and kappa opioid receptors in vitro. However, the extent to which these receptors contribute to (S)-ketamine's in vivo pharmacology is unknown. We investigated the extent to which (S)-ketamine interacts with opioid receptors in rats by combining in vitro and in vivo pharmacological approaches, in vivo molecular and functional imaging, and behavioral procedures relevant to human abuse liability. We found that the preferential opioid receptor antagonist naltrexone decreased (S)-ketamine self-administration and (S)-ketamine–induced activation of the nucleus accumbens, a key brain reward region. A single reinforcing dose of (S)-ketamine occupied brain MORs in vivo, and repeated doses decreased MOR density and activity and decreased heroin reinforcement without producing changes in NMDA receptor or kappa opioid receptor density. These results suggest that (S)-ketamine's abuse liability in humans is mediated in part by brain MORs. [ABSTRACT FROM AUTHOR]

The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT 2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16–30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT 2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. Following d-amphetamine administration, frontal nondisplaceable binding potential (BP ND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p <.001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBP ND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p =.041). This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE. [ABSTRACT FROM AUTHOR]

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Positron emission tomography is a highly sensitive molecular imaging modality, based on the coincident detection of annihilation photons after positron decay. The most used detector is based on dense, fast, and luminous scintillators read out by light sensors. This review covers the various detector concepts for clinical and preclinical systems. [ABSTRACT FROM AUTHOR]

Fluid transport in cementitious matrices and materials is fundamental for many engineering and environmental applications. However, observing and measuring transport processes inside opaque porous solids, such as cement, is technically challenging. We tested the feasibility of using Positron Emission Tomography (PET) for in-situ tracking of fluid being spontaneously imbibed into cementitious matrices. We found that the 124I radiotracer enables tracking of the 3D spatiotemporal distribution of the fluids moving through the solid phase. Our measurements show a similar transport rate for Ordinary Portland (CEM І) and slag (CEM ІІІ/B) cement pastes. For both cement types, we found that the fluid penetration depth is proportional to t 0.25. Such a relationship indicates anomalous transport and agrees with standard imbibition/sorptivity experiments. This result confirms that the method offers a reliable technique to explore transport phenomena in cementitious materials. [ABSTRACT FROM AUTHOR]

This research presents a new method for studying gas-water two-phase flow in fractured coal, integrating cutting-edge imaging techniques. We combine dynamic positron emission tomography (PET), high-resolution X-ray micro-computed tomography (micro-CT), and unsteady-state fluid flow experiments. First, micro-CT under reservoir pressure conditions maps the sample's fracture structure at high-resolution. Then, helium injection into a water-saturated sample simulates gas flow in a coal seam during production. Real-time PET monitoring captures the dynamic displacement process within the fractures. This approach yields crucial data on gas injection volume, pressure variations, and water production, enabling relative permeability curve prediction. Finally, multi-scale image analysis merges high-resolution micro-CT with dynamic PET images, overlaying the flow path onto the fracture network. This innovative method leverages the strengths of both PET and micro-CT, offering unprecedented visualization of gas-water flow behaviour in fractured coal. PET images play a crucial role in providing both spatial and temporal water saturation profiles since the activity mapping directly correlates with water volume distribution in the fractures. The consistency between the initial activity profile along the sample from PET and the fracture volume distribution calculated from micro-CT images confirms the reliability of PET data. The workflow proposed in this paper can be used to monitor two phase flow displacement in unconventional rocks such as coal and be applied for determination of relative permeability curves. • Multi-instrumental imaging is employed to understand coal relative permeability. • PET imaging offers real-time visualization, revealing the dynamic of fluid flow in fractures. • Multi-scale analysis of PET and micro-CT offers a novel method for flow in complex coal fractures. [ABSTRACT FROM AUTHOR]

Mechanistic understanding and prediction of solute transport and surface reactions in the pore space of rocks and soils is critical for a variety of processes, including sediment diagenesis, contaminant remediation, and long-term waste storage strategies. Positron emission tomography (PET) using β+-emitting radiotracers is an established and reliable method for investigating advective flow and diffusive flux in porous geomaterials. Here we present a conceptual strategy for spatially resolved quantification of crystal surface reactivity for sorption reactions based on PET techniques. The deconvolution of tracer breakthrough curves quantifies the sorption of F− tracer on calcite crystal surfaces and identifies the varying surface reactivity in the complex porous material. Using an artificial sediment as a model system, we demonstrate the quantifiability of sorption effects down to 10 pmol/mm3. The proposed strategy outlines how spatially resolved surface reactivities and their temporal changes over time can generally be determined using PET. • Positron emission tomography (PET) is used to quantify the surface reactivity in porous media. • PET allows identification of both reactivity and flow field of reactive transport processes. • Fluorine-18 used as reactive tracer for porous carbonate materials. [ABSTRACT FROM AUTHOR]

One of the pathologic hallmarks of Alzheimer's disease (AD) is neurofibrillary tau tangles. Despite our knowledge that tau typically initiates in the medial temporal lobe (MTL), the mechanisms driving tau to spread beyond MTL remain unclear. Emerging evidence reveals distinct patterns of functional connectivity change during aging and preclinical AD: while connectivity within-network decreases, connectivity between-network increases. Building upon increased between-network connectivity, our study hypothesizes that this increase may play a critical role in facilitating tau spread in early stages. We conducted a longitudinal study over two to three years intervals on a cohort of 46 healthy elderly participants (mean age 64.23 ± 3.15 years, 26 females). Subjects were examined clinically and utilizing advanced imaging techniques that included resting-state functional MRI (rs-fMRI), structural magnetic resonance imaging (MRI), and a second-generation positron emission tomography (PET) tau tracer, 18F-MK6240. Through unsupervised agglomerative clustering and increase in between-network connectivity, we successfully identified individuals at increased risk of future tau elevation and AD progression. Our analysis revealed that individuals with increased between-network connectivity are more likely to experience more future tau deposition, entorhinal cortex thinning, and lower selective reminding test (SRT) delayed scores. Additionally, in the limbic network, we found a strong association between tau progression and increased between-network connectivity, which was mainly driven by beta-amyloid (Aβ) positive participants. These findings provide evidence for the hypothesis that an increase in between-network connectivity predicts future tau deposition and AD progression, also enhancing our understanding of AD pathogenesis in the preclinical stages. [ABSTRACT FROM AUTHOR]

Trop-2 is closely related to the development and progression of a variety of tumours and poor prognosis. This study aimed to construct an iodine-124 (124I)-labelled antibody-drug conjugate (ADC) positron emission tomography (PET) probe which could noninvasively image Trop-2 in vivo , providing an important method for the diagnosis of tumours with high Trop-2 expression in clinical practice and monitoring their treatment. In this study, a novel Trop-2-targeting molecular probe, 124I-IMMU-132, was constructed to better reveal the expression of Trop-2. The targeting and binding abilities of the probe to Trop-2-positive tumours were investigated in Capan-1/MDA-MB-468/Mcf-7 cells and their animal models. The constructed 124I-IMMU-132 probe maintained both reliable radiochemical characteristics and binding affinity (K d = 2.200 nmol/L). The uptake of the probe by Trop-2-positive Capan-1/MDA-MB-468 cells increased in a time-dependent manner. The probe bound specifically to Capan-1/MDA-MB-468 tumours in vivo. The SUVmax Tumour/muscle ratio gradually increased with time, from 4.30 ± 0.55–10.78 ± 1.80 (p < 0.01) in the Capan-1 model and from 8.84 ± 0.95–32.20 ± 2.9 (p < 0.001) in the MDA-MB-468 model. The biodistribution and pharmacokinetics of 124I-IMMU-132 in a mouse model were consistent with the imaging results, and the dosimetry estimation in humans was acceptable. 124I-IMMU-132 PET is a promising imaging technique for delineating Trop-2-positive tumours. It has great potential in early diagnosis and targeted selection of patients that could benefit from its application. [Display omitted] • The non-invasive Trop-2 detection probe 124I-IMMU-132 was firstly constructed. • The first to construct a radioactive probe using ADC drug IMMU-132. • The first to construct a Trop-2 targeted probe using 124I. [ABSTRACT FROM AUTHOR]

Stimulants represent the first line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) and are among the most prescribed psychopharmacological treatments. Their mechanism of action at synaptic level has been extensively studied. However, it is less clear how their mechanism of action determines clinically observed benefits. To help bridge this gap, we provide a comprehensive review of stimulant effects, with an emphasis on nuclear medicine and magnetic resonance imaging (MRI) findings. There is evidence that stimulant-induced modulation of dopamine and norepinephrine neurotransmission optimizes engagement of task-related brain networks, increases perceived saliency, and reduces interference from the default mode network. An acute administration of stimulants may reduce brain alterations observed in untreated individuals in fronto-striato-parieto-cerebellar networks during tasks or at rest. Potential effects of prolonged treatment remain controversial. Overall, neuroimaging has fostered understanding on stimulant mechanism of action. However, studies are often limited by small samples, short or no follow-up, and methodological heterogeneity. Future studies should address age-related and longer-term effects, potential differences among stimulants, and predictors of treatment response. • Stimulants modulate dopamine and norepinephrine neurotransmission. • This enhances task-related brain networks and suppresses the default-mode network. • A single dose may reduce functional alterations observed in untreated individuals. • Potential longer-term effects need further investigation. • Future studies should clarify features predictive of treatment response. [ABSTRACT FROM AUTHOR]

The dopamine (DA) hypothesis postulates hyperactivity of subcortical DA transmission and hypoactivity of cortical DA in schizophrenia (SCH). Positron emission tomography provides the ability to assess this hypothesis in humans. However, no studies have examined the relationship between cortical DA and striatal DA in this illness. D 2/3 receptor radiotracer [11C]FLB457 BP ND (binding potential relative to nondisplaceable uptake) was measured in 14 off-medication subjects with SCH and 14 healthy control (HC) subjects at baseline and after the administration of 0.5 mg/kg oral d-amphetamine. The amphetamine-induced change in BP ND (ΔBP ND) was calculated as the difference between BP ND in the postamphetamine condition and BP ND in the baseline condition and expressed as a percentage of BP ND at baseline. DA release in the striatum using the radiotracer [11C]NPA was also measured in these subjects. [11C]FLB457 ΔBP ND was greater in the HC group compared with the SCH group (F 1,26 = 5.7; p =.02) with significant differences in [11C]FLB457 ΔBP ND seen across cortical brain regions. Only in the SCH group was a significant negative correlation observed between [11C]FLB457 ΔBP ND in the dorsolateral prefrontal cortex and [11C]NPA ΔBP ND in the dorsal caudate (r = −0.71, p =.005). Subjects with SCH demonstrated deficits of DA release in cortical brain regions relative to HC subjects. Examining both cortical and striatal DA release in the same subjects demonstrated an inverse relationship between cortical DA release and striatal DA release in SCH not present in HC subjects, providing support for the current DA hypothesis of SCH. [ABSTRACT FROM AUTHOR]

Colony stimulating factor 1 receptor (CSF-1R) is a kinase expressed on macrophages and microglia in the brain. It has been recognized as a potential drug and imaging target in treatment of neuroinflammatory diseases and glioblastoma. Despite several attempts, no validated CSF-1R PET tracer is currently available. The aim of this work was to develop a brain permeable CSF-1R PET tracer for non-invasive imaging of CSF-1R in vivo. Based on fragments of two potent and selective CSF-1R inhibitors, novel hybrid molecules were designed and synthesized. Affinity for human recombinant CSF-1R and selectivity over c-KIT and PDGFR-β was determined using a FRET based in vitro assay. Radiosynthesis was performed by fully automated [11C]CH 3 I methylation of the corresponding des -methyl precursor. PET imaging was performed at baseline, efflux transporter blocking and CSF-1R blocking conditions. Moreover, tracer distribution and blood and plasma radiometabolites were determined following injection in healthy mice. The most promising CSF-1R inhibitor, compound 4 , showed high selectivity and high affinity for CSF-1R (IC 50 : 12 ± 3 nM) and no affinity for kinase family members c-KIT and PDGFR-beta. [11C] 4 was obtained in good yield (15 ± 0.2 % decay corrected yield, (2.0 ± 0.26 GBq at end of synthesis) and excellent purity. The compound demonstrated high brain penetration and good metabolic stability (>2 %ID/g at 60 min post injection and 79 ± 8 % intact [11C] 4 in brain at 60 min post injection) and no strong efflux transporter substrate behavior. Blocking CSF-1R prior to imaging with [11C] 4 resulted in significant decrease in brain uptake. In conclusion, [11C] 4 shows good potential as a novel PET tracer for imaging of CSF-1R in the CNS and future experiments in relevant animal models are warranted. [Display omitted] [ABSTRACT FROM AUTHOR]

• Image restoration algorithm to incorporate denoising and deblurring methods. • Our proposed algorithm can improve diagnostic accuracy for Alzheimer's disease. • Improving the image quality of Alzheimer's disease using the PET image with ADNI. • Numerous evaluations in the field are taking advantage of our algorithm. The aim of this study was to design an image restoration algorithm that combined denoising and deblurring and to confirm its applicability in positron emission tomography (PET) images of patients with Alzheimer's disease (AD). PET images of patients with AD obtained using 18F-AV-45, which have a lot of noise, and 18F-FDG, which have a lot of blurring, were available in the Alzheimer's Disease Neuroimaging Initiative open dataset. The proposed framework performed image restoration incorporating blind deconvolution after noise reduction using a non-local means (NLM) approach to improve the PET image quality. We found that the coefficient of variation result after denoising and deblurring of the 18F-AV-45 image was improved 1.34 times compared to that for the degraded image. In addition, the profile result of the 18F-FDG PET image of patients with AD, which had a relatively large amount of blurring, showed a gentle shape when deblurring was performed after denoising. The overall no-reference-based evaluation results showed different results according to the degree of noise and blurring in the PET images. In conclusion, the applicability of the deconvolution deblurring algorithm to AD PET images after NLM denoising processing was demonstrated in this study. [ABSTRACT FROM AUTHOR]

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Prostate cancer (PCa) is one of the most common tumors in men, with the overexpression of prostate-specific membrane. In this study, we developed four new 68Ga-labeled PSMA-targeting tracers by introducing quinoline, phenylalanine and decanoic acid groups to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Four radiotracers were synthesized with radiochemical purity >95 %, and exhibited high stability in vivo and in vitro. The inhibition constants (K i) of SDTWS01-04 to PSMA were in the nanomolar range (<10 nM). Micro PET/CT imaging and biodistribution analysis revealed that 68Ga-SDTWS01 enabled clear tumor visualization in PET images at 1.5 h post-injection, with excellent pharmacokinetic properties. Notably, the kidney uptake of 68Ga-SDTWS01 significantly reduced, with higher tumor-to-kidney ratio (0.36 ± 0.02), tumor-to-muscle ratio (24.31 ± 2.10), compared with 68Ga-PSMA-11 (T/K: 0.15 ± 0.01; T/M: 14.97 ± 1.40), suggesting that 68Ga-SDTWS01 is a promising radiotracer for the diagnosis of PCa. Moreover, SDTWS01 with a chelator DOTA could also label 177Lu and 225Ac, which could be used for the treatment of PCa. [Display omitted] • Four novel radiotracers were developed. • 68Ga-SDTWS01 displayed reduced kidney uptake, with high T/K and T/M ratios. • 68Ga-SDTWS01 is a promising radiotracer for the diagnosis of PCa. [ABSTRACT FROM AUTHOR]

[Display omitted] Although α2 was the first neuronal nicotinic acetylcholine receptor (nAChR) receptor subunit to be cloned, due to its low level of expression in rodent brain, its study has largely been neglected. This study provides a comparison of the α2 and α4 structures and their functional similarities, especially in regard to the existence of low and high sensitivity forms based on subunit stoichiometry. We show that the pharmacological profiles of the low and high sensitivity forms of α2β2 and α4β2 receptors are very similar in their responses to nicotine, with high sensitivity receptors showing protracted responses. Sazetidine A, an agonist that is selective for the high sensitivity α4 receptors also selectively activates high sensitivity α2 receptors. Likewise, α2 receptors have similar responses as α4 receptors to the positive allosteric modulators (PAMs) desformylflustrabromine (dFBr) and NS9283. We show that the partial agonists for α4β2 receptors, cytisine and varenicline are also partial agonists for α2β2 receptors. Studies have shown that levels of α2 expression may be much higher in the brains of primates than those of rodents, suggesting a potential importance for human therapeutics. High-affinity nAChR have been studied in humans with PET ligands such as flubatine. We show that flubatine has similar activity with α2β2 and α4β2 receptors so that α2 receptors will also be detected in PET studies that have previously presumed to selectively detect α4β2 receptors. Therefore, α2 receptors need more consideration in the development of therapeutics to manage nicotine addiction and declining cholinergic function in age and disease. [ABSTRACT FROM AUTHOR]

As the demand for 68Ga continues to grow, there is increasing interest in single-to-multi-Curie production quantities of both [68Ga]GaCl 3 and tracers such as [68Ga]Ga-PSMA-11. While such quantities are possible with solid targets, this implementation is often challenging as it typically requires significant site expertise for solid target processing and careful operator-dependent synchronization of multiple independent time-sensitive chemistry steps. Herein we focus on a fully automated solid target production and purification process whereby we avoid the need for tongs/tele-pliers, and have simplified the chemistry by implementing a single sequence (i.e. "time-list") to execute cassette-based dissolution, purification, and labeling. Electroplated 68Zn was irradiated in a PETtrace prototype automated solid target system. Following irradiation, and using a single FASTlab time-list, the 68Zn was automatically dissolved with HCl/H 2 O 2 and purified as [68Ga]GaCl 3 using a combination of resins (ZR/TK400, A8, TK200: Triskem). For select experiments, [68Ga]Ga-PSMA-11 was also produced on the same cassette/single time-list (N = 4), or, by kit labeling (N = 1). Efforts focused towards on-cassette production of [68Ga]GaCl 3 strived to maximize activity and quality, whereas efforts focused towards on-cassette production of [68Ga]Ga-PSMA-11 aimed at limiting the entire production cycle to 1 h including the irradiation time (i.e. start-of-bombardment ➔ end-of-synthesis [EOS]). For the high activity triplicate [68Ga]GaCl 3 productions (i.e. 80 μA, 102 min, 216 ± 10 mg), [68Ga]GaCl 3 was purified (end-of-bombardment ➔ end-of-purification [EOP]) in ~28 min with activity yields of 181 ± 8 GBq at EOP and average radiochemical yields of 66 ± 5%. Average AMAs of 2.26 ± 0.16 TBq/μmol using DOTA (N = 3) and 12.00 TBq/μmol using HBED (PSMA-11) (N = 1) at EOP were measured. For the single kit test, (80 μA, 120 min, 263 mg 68Zn) for which 18 mg ascorbic acid was added to the buffer, 199 GBq of [68Ga]Ga-PSMA-11 was successfully produced (thin layer chromatography-based radiochemical purity >99% at 6 h EOS). Finally, for efforts focused at expedient [68Ga]Ga-PSMA-11, up to 42 GBq [68Ga]Ga-PSMA-11 with a radiochemical yield of 51.2% was produced in 63 min, including beamtime, using 220 mg of 68Zn as target material. With the goal of simplifying solid target production and purification efforts, automated methods using single-use, cassette-based approaches for rapid, large-scale, single time-list production of [68Ga]GaCl 3 and [68Ga]Ga-PSMA-11 were developed. These methods were simple to execute and yielded high quality multi-Curie levels of both [68Ga]GaCl 3 and [68Ga]Ga-PSMA-11. [Display omitted] • 42 GBq (>1 Ci) [68Ga]Ga-PSMA-11 in 1 h including beam time (i.e. SOB ➔ EOS) • ~200 GBq (>5 Ci) of [68Ga]Ga-PSMA-11 with a preliminary kit test • 385 GBq (>10 Ci) total 68Ga production using a fully automated target system • High quality [68Ga]GaCl 3 with DOTA-based AMA up to 2.4 TBq/μmol at EOP • Cassette-based dissolution, purification, and labeling using a single time-list [ABSTRACT FROM AUTHOR]

Further diagnostic testing may be required after a coronary computed tomography angiography (CTA) showing suspected coronary stenosis. Whether myocardial perfusion imaging (MPI) provides further prognostic information post-CTA remains debated. We evaluated the prognosis for patients completing CTA stratified for post-CTA diagnostic work-up using real-world data. We identified all patients in our uptake area with angina symptoms undergoing first-time CTA over a 10-year period. Follow-up time was a median of 3.7 years [1.9–5.8]. The primary endpoint was a composite of myocardial infarction or death. The secondary endpoint was late revascularization. During the study period 53,351 patients underwent CTA. Of these, 24% were referred for further down-stream testing, 3,547 (7%) to MPI and 9,135 (17%) to invasive coronary angiography (ICA). The primary and secondary endpoints occurred in 2,026 (3.8%) and 954 (1.8%) patients. Patient-characteristic-adjusted hazard ratios for the primary and secondary endpoint using patients with a normal CTA as reference were 1.37 (1.21–1.55) and 2.50 (1.93–3.23) for patient treated medically, 1.68 (1.39–2.03) and 6.13 (4.58–8.21) for patients referred to MPI and 1.94 (1.69–2.23) and 9.18 (7.16–11.78) for patients referred for ICA, respectively. Adjusted analysis with stratification for disease severity at CTA showed similar hazard ratios for patients treated medically after CTA and patients referred for MPI and treated medically after the MPI. In patients completing coronary CTA, second-line MPI testing seems to identify patients at low risk of future events. MPI seems to have the potential to act as gatekeeper for ICA after coronary CTA. Condensed abstract: The prognostic impact of using myocardial perfusion imaging as a gatekeeper after coronary computed tomography angiography (CTA) to avoid unnecessary invasive coronary angiography has not been investigated.From a regional Danish population-based clinical registry, we retrospectively identified 53,709 patients who underwent coronary CTA. Patients were categorized based on the coronary CTA results and the post-coronary CTA diagnostic work-up with either myocardial perfusion imaging or invasive coronary angiography.The study demonstrated that in patients completing coronary CTA, second-line myocardial perfusion testing seems to identify patients at low risk of future events. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

The hypothesis of chronically low brain serotonin levels as pathophysiologically linked to impulsive aggression has been around for several decades. Whereas the theory was initially based on indirect methods to probe serotonin function, our understanding of the neural mechanisms involved in impulsive aggression has progressed with recent advances in neuroimaging. The review integrates evidence based on data from several neuroimaging domains in humans. In vivo molecular neuroimaging findings demonstrate associations between impulsive aggression and high serotonin 1B and serotonin 4 receptor binding, high serotonin transporter levels, and low monoamine oxidase A levels, suggesting that low interstitial serotonin levels are a neurobiological risk factor for impulsive aggressive behavior. Imaging genetics suggests that serotonergic-related genetic polymorphisms associate with antisocial behavior, and some evidence indicates that the low-expressing monoamine oxidase A genotype specifically predisposes to impulsive aggression, which may be mediated by effects on corticolimbic function. Interventions that (presumably) alter serotonin levels have effects on brain activity within brain regions involved in impulsive aggression, notably the amygdala, dorsal striatum, anterior cingulate, insula, and prefrontal cortex. Based on these findings, we propose a model for the modulatory role of serotonin in impulsive aggression. Future studies should ensure that clinical features unique for impulsive aggression are appropriately assessed, and we propose investigations of knowledge gaps that can help confirm, refute, or modify our proposed model of impulsive aggression. [ABSTRACT FROM AUTHOR]

Although a number of neuroimaging biomarkers for response have been proposed, none have been tested prospectively for direct effects on treatment outcomes. To the best of our knowledge, this is the first prospective test of the clinical utility of the use of an imaging biomarker to select treatment for patients with major depressive disorder. Eligible participants (n = 60) had a primary diagnosis of major depressive disorder and were assigned to either escitalopram or cognitive behavioral therapy based on fluorodeoxyglucose positron emission tomography activity in the right anterior insula. The overall study remission rate after 12 weeks of treatment, based on the end point Hamilton Depression Rating Scale score, was then examined for futility and benefit of the strategy. Remission rates demonstrated lack of futility at the end of stage 1 (37%, 10/27), and the study proceeded to stage 2. After adjustment for the change in stage 2 sample size, the complete remission rate did not demonstrate evidence of benefit (37.7%, 95% confidence interval, 26.3%–51.4%, p =.38). However, total remission rates (complete and partial remission) did reach significance in post hoc analysis (49.1%, 95% confidence interval, 37.6%–60.7%, p =.020). The study shows some evidence for a role of the right anterior insula in the clinical choice of major depressive disorder monotherapy. The effect size, however, is insufficient for the use of insula activity as a sole predictive biomarker of remission. The study also demonstrates the logistical difficulties in establishing clinical utility of biomarkers. [ABSTRACT FROM AUTHOR]

Imaging tools are potentially able to provide valuable data regarding the development of an efficient vaccine against viral diseases. Tracking immune cells in vivo by imaging modalities can help us understand the intrinsic behaviors of immune cells in response to vaccine components. Imaging patterns at the vaccination site and draining lymph nodes might provide useful information about the vaccine potency. Besides, serial lung CT imaging has been purposed to evaluate vaccine efficiency regarding its protection against typical lung lesions of viral pneumonias. On the other hand, vaccination causes various confusing radiologic patterns that pose diagnostic challenges for clinicians and pitfalls for reading radiologists. This manuscript reviews potential applications of imaging modalities in the process of vaccine development and also goes over some of the imaging findings/pitfalls following vaccination. • Imaging tools could track the immune cell dynamics in vivo, which holds valuable research attention in the vaccination field. • Serial CT imaging might be a great indicator of vaccine efficiency in research setting. • Vaccination causes various confusing radiologic patterns that pose diagnostic challenges for clinicians and radiologists. [ABSTRACT FROM AUTHOR]

As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound, which was then radiolabeled with fluorine-18 via a facile S N Ar reaction to form 2-[18F]fluoropyridine scaffold. Good blood–brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [18F] 14 (also named as [18F]MAGL-1902). This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers. A highly potent irreversible MAGL PET tracer [18F] 14 was described, which exhibited favorable in vitro and in vivo characteristics, including excellent affinity, high brain uptake, and good binding specificity. [Display omitted] [ABSTRACT FROM AUTHOR]

The utilization of Monte Carlo simulation is a highly effective method in advancing research within the field of nuclear medicine. An important software tool for simulating and modeling cutting-edge systems for Positron Emission Tomography (PET) is the Geant4 Application for Tomographic Emission (GATE). This research specifically concentrates on two Siemens PET scanners: the Siemens Biograph True point (True V) and Siemens Biograph mcT 20 excel. Our primary objective was to validate the GATE V8.2 simulation in accordance with the NEMA (National Electrical Manufacturers Association) NU 2-2018 protocol, using a parallel computing platform on a local cluster of computers. This cluster was managed by the open-source package TORQUE version 6.1.0, which is based on the original wrapper PBS. The results of this validation process for the Siemens Biograph True point (True V) scanner were highly promising. The scatter fraction (SF), peak noise equivalent count rate (NECR), and sensitivity all demonstrated a remarkable level of agreement, with deviations within 10.02%, 5.4%, and 1.57%, respectively. Additionally, the spatial resolution was found to deviate by less than 0.59 mm. Image evaluations demonstrate high-quality results for both Siemens Biograph True point (True V) and Siemens Biograph mcT 20 excel scanners, validating the GATE simulation. The study on acquisition time provides insights into optimizing computing simulation time. This research demonstrates the effectiveness of Monte Carlo simulation, facilitated by GATE, in accurately modeling advanced PET systems. The validation results affirm the reliability of GATE V8.2 in accordance with NEMA standards for the Siemens Biograph True point (True V) scanner. The high-quality images obtained from GATE-validated scanners underscore the potential of this simulation approach in advancing nuclear medicine research. Additionally, the study on acquisition time provides valuable considerations for optimizing simulation efficiency. • GATE Software: Key for PET system simulation. • The SF, NECR, Sensitivity and SR are validated for Biograph True Point • High image quality of two Biograph scanners confirmed by GATE • Attenuation and scatter correction accuracy validated. • Acquisition Time Optimization: reducing simulation time while preserving IQ. [ABSTRACT FROM AUTHOR]

Low resolution of positron emission tomography (PET) limits its diagnostic performance. Deep learning has been successfully applied to achieve super-resolution PET. However, commonly used supervised learning methods in this context require many pairs of low- and high-resolution (LR and HR) PET images. Although unsupervised learning utilizes unpaired images, the results are not as good as that obtained with supervised deep learning. In this paper, we propose a quasi-supervised learning method, which is a new type of weakly-supervised learning methods, to recover HR PET images from LR counterparts by leveraging similarity between unpaired LR and HR image patches. Specifically, LR image patches are taken from a patient as inputs, while the most similar HR patches from other patients are found as labels. The similarity between the matched HR and LR patches serves as a prior for network construction. Our proposed method can be implemented by designing a new network or modifying an existing network. As an example in this study, we have modified the cycle-consistent generative adversarial network (CycleGAN) for super-resolution PET. Our numerical and experimental results qualitatively and quantitatively show the merits of our method relative to the state-of-the-art methods. The code is publicly available at https://github.com/PigYang-ops/CycleGAN-QSDL. • Supervised learning methods for super-resolution PET require pairs of low- and high-resolution (LR and HR) PET images. • Quasi-supervised learning is a new type of weakly-supervised learning that can recover HR PET images from LR counterparts by leveraging similarity between unpaired LR and HR image patches. • Our proposed method can be implemented by designing a new network or modifying an existing network. • The experimental results qualitatively and quantitatively show the merits of our method relative to the state-of-the-art methods. [ABSTRACT FROM AUTHOR]

Conflicting evidence exists on the relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) biomarkers. Therefore, we conducted a random-effects meta-analysis to evaluate the correlation of glucose metabolism measures (glycated hemoglobin, fasting blood glucose, insulin resistance indices) and DM status with AD biomarkers of amyloid-β and tau measured by positron emission tomography or cerebrospinal fluid. We selected 37 studies from PubMed and Embase, including 11,694 individuals. More impaired glucose metabolism and DM status were associated with higher tau biomarkers (r=0.11[0.03–0.18], p=0.008; I2=68%), but were not associated with amyloid-β biomarkers (r=-0.06[-0.13–0.01], p=0.08; I2=81%). Meta-regression revealed that glucose metabolism and DM were specifically associated with tau biomarkers in population settings (p=0.001). Furthermore, more impaired glucose metabolism and DM status were associated with lower amyloid-β biomarkers in memory clinic settings (p=0.004), and in studies with a higher prevalence of dementia (p<0.001) or lower cognitive scores (p=0.04). These findings indicate that DM is associated with biomarkers of tau but not with amyloid-β. This knowledge is valuable for improving dementia and DM diagnostics and treatment. • Impaired glucose metabolism and DM status were associated with higher tau biomarkers. • Impaired glucose metabolism and DM status were not related to amyloid-β biomarkers. • Associations were different in sub-populations of setting and cognitive status. • Factors underlying the heterogeneity between studies should be further explored. [ABSTRACT FROM AUTHOR]

The deuterium labelling of pharmaceuticals is a useful strategy for altering pharmacokinetic properties, particularly for improving metabolic resistance. The pharmacological effects of such metabolites are often assumed to be negligible during standard drug discovery and are factored in later at the clinical phases of development, where the risks and benefits of the treatment and side-effects can be wholly assessed. This paradigm does not translate to the discovery of radiopharmaceuticals, however, as the confounding effects of radiometabolites can inevitably show in preliminary positron emission tomography (PET) scans and thus complicate interpretation. Consequently, the formation of radiometabolites is crucial to take into consideration, compared to non-radioactive metabolites, and the application of deuterium labelling is a particularly attractive approach to minimise radiometabolite formation. Herein, we provide a comprehensive overview of the deuterated carbon-11 and fluorine-18 radiopharmaceuticals employed in PET imaging experiments. Specifically, we explore six categories of deuterated radiopharmaceuticals used to investigate the activities of monoamine oxygenase (MAO), choline, translocator protein (TSPO), vesicular monoamine transporter 2 (VMAT2), neurotransmission and the diagnosis of Alzheimer's disease; from which we derive four prominent deuteration strategies giving rise to a kinetic isotope effect (KIE) for reducing the rate of metabolism. Synthetic approaches for over thirty of these deuterated radiopharmaceuticals are discussed from the perspective of deuterium and radioisotope incorporation, alongside an evaluation of the deuterium labelling and radiolabelling efficacies across these independent studies. Clinical and manufacturing implications are also discussed to provide a more comprehensive overview of how deuterated radiopharmaceuticals may be introduced to routine practice. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Carbonic anhydrase-IX (CA-IX) is markedly overexpressed in many types of solid tumors promoting tumorigenicity and tumor growth. We synthesized novel 68Ga-labeled imidazothiadiazole sulfonamide (IS) derivatives (68Ga]Ga-DO3A-IS1 and 68Ga]Ga-DO2A-IS2), and evaluated their utility as positron emission tomography (PET) probes targeting CA-IX. 67/68Ga]Ga-DO3A-IS1 and 67/68Ga]Ga-DO2A-IS2 were synthesized from corresponding precursors by ligand substitution reaction in acetate buffer. Cell binding assays were performed using HT-29 cells, which highly express CA-IX, and MDA-MB-231 cells, which show lower-level expression of CA-IX, and a biodistribution assay with model mice bearing the HT-29 or MDA-MB-231 tumor was performed. 68Ga]Ga-DO3A-IS1 was further evaluated by PET/CT. To evaluate their fundamental properties, 67Ga]Ga-DO3A-IS1 and 67Ga]Ga-DO2A-IS2 were synthesized by conjugation with 67Ga, which has a much longer decay half-life and can be utilized more easily than 68Ga. 67/68Ga]Ga-DO3A-IS1 and 67/68Ga]Ga-DO2A-IS2 were prepared from corresponding precursors with preferable yield and purity. 67Ga]Ga-DO3A-IS1 and 67Ga]Ga-DO2A-IS2 showed significantly greater binding to HT-29 cells than MDA-MB-231 cells in vitro and the binding of 67Ga]Ga-DO2A-IS2 to HT-29 cells was much greater than that of 67Ga]Ga-DO3A-IS1, suggesting multivalent interactions. 67Ga]Ga-DO3A-IS1 and 67Ga]Ga-DO2A-IS2 showed significant selectivity for the HT-29 tumor in vivo , while tumor uptake of 67Ga]Ga-DO3A-IS1 was greater than that of 67Ga]Ga-DO2A-IS2. PET/CT of 68Ga]Ga-DO3A-IS1 showed selectivity for the HT-29 tumor, although 68Ga]Ga-DO3A-IS1 could not be used to visualize the HT-29 tumor clearly because of its strong background signals. These results indicate that 68Ga-labeled IS derivatives may be useful 68Ga-PET probes targeting CA-IX with further structural modifications. [ABSTRACT FROM AUTHOR]

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases. The 18 kDa translocator protein (TSPO) expression in the central nervous system is upregulated in response to glial cell activation. There is a great potential for the future application of TSPO radioligands as diagnostic and prognostic tools, as well as for assessing therapeutic interventions for neurologic diseases. Image 1 [ABSTRACT FROM AUTHOR]

• Lesion detectability was not lost using proposed low-dose PET-CT protocol. • Low-dose PET-CT protocol reduces radiation exposure to 43% of standard protocol. • Machine-learning increased lesion contrast and reduced false positives. • Machine-learning enables radiation exposure reduction to 34% of standard protocol. To conduct a simplified lesion-detection task of a low-dose (LD) PET-CT protocol for frequent lung screening using 30% of the effective PETCT dose and to investigate the feasibility of increasing clinical value of low-statistics scans using machine learning. We acquired 33 SD PET images, of which 13 had actual LD (ALD) PET, and simulated LD (SLD) PET images at seven different count levels from the SD PET scans. We employed image quality transfer (IQT), a machine learning algorithm that performs patch-regression to map parameters from low-quality to high-quality images. At each count level, patches extracted from 23 pairs of SD/SLD PET images were used to train three IQT models – global linear, single tree, and random forest regressions with cubic patch sizes of 3 and 5 voxels. The models were then used to estimate SD images from LD images at each count level for 10 unseen subjects. Lesion-detection task was carried out on matched lesion-present and lesion-absent images. LD PET-CT protocol yielded lesion detectability with sensitivity of 0.98 and specificity of 1. Random forest algorithm with cubic patch size of 5 allowed further 11.7% reduction in the effective PETCT dose without compromising lesion detectability, but underestimated SUV by 30%. LD PET-CT protocol was validated for lesion detection using ALD PET scans. Substantial image quality improvement or additional dose reduction while preserving clinical values can be achieved using machine learning methods though SUV quantification may be biased and adjustment of our research protocol is required for clinical use. [ABSTRACT FROM AUTHOR]

Radiolabeled peptides play a central role in nuclear medicine as radiotheranostics for targeted imaging and therapy of cancer. We have recently proposed the use of metabolically stabilized GRPR antagonist BBN2 for radiolabeling with 18F and 68Ga and subsequent PET imaging of GRPRs in prostate cancer. The present work studied the impact of 44gSc- and 68Ga-labeled DOTA complexes attached to GRPR antagonist BBN2 on the in vitro GRPR binding affinity, and their biodistribution and tumor uptake profiles in MCF7 breast and PC3 prostate cancer models. DOTA-Ava-BBN2 was radiolabeled with radiometals 68Ga and 44gSc. Gastrin-releasing peptide receptor (GRPR) affinities of peptides were assessed in PC3 prostate cancer cells. GRPR expression profiles were studied in human breast cancer tissue samples and MCF7 breast cancer cells. PET imaging of 68Ga- and 44gSc-labeled peptides was performed in MCF7 and PC3 xenografts as breast and prostate cancer models. Radiopeptides [68Ga]Ga-DOTA-Ava-BBN2 and [44gSc]Sc-DOTA-Ava BBN2 were prepared in radiochemical yields of 70–80% (decay-corrected), respectively. High binding affinities were found for both peptides (IC 50 = 15 nM (natGa) and 5 nM (natSc)). Gene expression microarray analysis revealed high GRPR mRNA expression levels in estrogen receptor (ER)-positive breast cancer, which was further confirmed with Western blot and immunohistochemistry. However, PET imaging showed only low tumor uptake of both radiotracers in MCF7 xenografts ([68Ga]Ga-DOTA-BBN2 (SUV 60min 0.27 ± 0.06); [44gSc]Sc-DOTA-BBN2 (SUV 60min 0.20 ± 0.03)). In contrast, high tumor uptake and retention were found for both radiopeptides in PC3 tumors ([68Ga]Ga-DOTA-BBN2 (SUV 60min 0.46 ± 0.07); [44gSc]Sc-DOTA-BBN2 (SUV 60min 0.51 ± 0.11)). Comparison of 68Ga- and 44gSc-labeled DOTA-Ava-BBN2 peptides revealed slight but noticeable differences of the radiometal with an impact on the in vitro GRPR receptor binding properties in PC3 cells. No differences were found in their in vivo biodistribution profiles in MCF7 and PC3 xenografts. Radiopeptides [68Ga]Ga-DOTA-Ava-BBN2 and [44gSc]Sc-DOTA-Ava-BBN2 displayed comparable tumor uptake and retention profiles with rapid blood and renal clearance profiles in both tumor models. The favorable PET imaging performance of [44gSc]Sc-DOTA-Ava-BBN2 in prostate cancer should warrant the development of an [43Sc]Sc-DOTA-Ava-BBN2 analog for clinical translation which comes with a main γ-line of much lower energy and intensity compared to 44gSc. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR) has emerged as an attractive target in the treatment of various cancers. Radiolabeled small molecules, antibodies, and peptides that specifically target EGFR are promising probes for tumor imaging to guide personalized treatment with EGFR-targeted drugs. This study aimed to radiolabel GE11 (an EGFR-specific targeting peptide) with 18-fluorine to develop a new EGFR-targeting positron emission tomography (PET) probe, [18F]FP-Lys-GE11, for imaging tumors overexpressing EGFR. [18F]FP-Lys-GE11 was produced by radiolabeling a GE11 peptide with the prosthetic group 4-nitrophenyl-2-[18F]fluoropropionate ([18F]NFP). Stability in PBS and mice serum, affinity for A431 cell line, U87 and PC-3 cells uptake and blocking studies, and biodistribution of [18F]FP-Lys-GE11 were determined. 2 h dynamic and static PET scans of probe for tumor-bearing mice normal and inhibition uptake were performed. [18F]FP-Lys-GE11 was stable in PBS and mice serum. The Kd and Bmax values of probe for A431 were 42.43 ± 3.75 nM and 3383 ± 81.73 CPM, respectively. In cell uptake and blocking experiments, a significant reduction in radioactivity accumulation (over 4-fold) was observed by blocking U87 and PC-3 cells with unlabeled peptide. PET imaging of U87 and PC-3 tumor-bearing mice revealed clear tumor imaging (tumor radioactivity accumulation was 3.48 ± 0.44 and 3.68 ± 0.76%ID/g respectively, tumor-to-muscle ratio was 3.45 ± 0.43 and 3.64 ± 0.76 respectively). Blocking imaging revealed that the U87 tumor uptake was significantly inhibited (2.21 ± 0.41%ID/g). The biodistribution and dynamic PET imaging showed that [18F]FP-Lys-GE11 was mainly excreted by the kidneys and the rest was excreted through the bile and intestines. The current results showed that [18F]FP-Lys-GE11was a good radiolabeled peptide probe for EGFR overexpression tumor's imaging. Unlabelled Image [ABSTRACT FROM AUTHOR]

To characterize the influence of apolipoprotein-E (APOE) genotype on cerebral Aβ load and longitudinal Aβ trajectories, 11C]Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging was used to assess amyloid load in a clinically heterogeneous cohort of 428 elderly participants with known APOE genotype. Serial 11C]PiB data and a repeated measures model were used to model amyloid trajectories in a subset of 235 participants classified on the basis of APOE genotype. We found that APOE-ε4 was associated with increased Aβ burden and an earlier age of onset of Aβ positivity, whereas APOE-ε2 appeared to have modest protective effects against Aβ. APOE class did not predict rates of Aβ accumulation. The present study suggests that APOE modifies Alzheimer's disease risk through a direct influence on amyloidogenic processes, which manifests as an earlier age of onset of Aβ positivity, although it is likely that other genetic, environmental, and lifestyle factors are important. • APOE-ε4 is associated with increased Aβ burden compared with other APOE genotypes. • Age of onset of Aβ positivity in APOE-ε4+ antecedes other genotypes by > 15 years. • APOE-ε2+ is associated with reduced Aβ burden and a delayed age of onset. • Within-genotype variability suggests additional factors influence Aβ trajectories. [ABSTRACT FROM AUTHOR]

We analyzed education, as a proxy of cognitive reserve, and the cholinergic pathway in Alzheimer's disease (AD), to test the hypothesis that education might modulate the relationship between clinical symptoms and metabolic and structural changes in AD. We included 84 subjects and compared between diagnostic groups and different educational levels the glucose metabolism of basal forebrain (BFM) and volume of the basal forebrain, the major cholinergic structure, and hippocampus (HM) (and hippocampal volume), a relevant projection site for the basal forebrain. Correlations with the global cognitive status and education in the whole sample were also performed. Patients with AD dementia showed reduced basal forebrain volume, hippocampal volume, and HM compared with controls. In the whole group, the global cognitive status was positively correlated with BFM and HM. Among high-educated subjects, mild cognitive impairment showed higher BFM and HM in comparison to other diagnostic groups. Our results suggest that in mild cognitive impairment subjects with a higher educational level, cholinergic activity is upregulated and this appears to have a compensatory effect, which may be lost in later symptomatic stages. • Higher basal forebrain metabolism characterizes highly educated patients with MCI. • Global cognition is positively associated with basal forebrain and hippocampal metabolism. • Upregulation of cholinergic activity might act as compensation in early stages of AD. [ABSTRACT FROM AUTHOR]

Gallium-68 is an important radionuclide for positron emission tomography (PET) with steadily increasing applications of 68Ga-based radiopharmaceuticals for clinical use. Current 68Ga sources are primarily 68Ge/68Ga-generators, along with successful attempts of 68Ga production using a cyclotron. This study evaluated cyclotron 68Ga production and automated separation using expeditiously manufactured solid targets, demonstrates an order of magnitude improvement in yield compared to 68Ge/68Ga generators, and presents a convenient alternative to existing cyclotron production processes. A comparison of radiolabeling and preclinical PET imaging was performed with both cyclotron and generator produced 68Ga. 100 mg enriched 68Zn (99.3% 68Zn, 0.48% 67Zn, 0.1% 66Zn) pellets pressed on silver discs were bombarded for 20–75 min using 12.5 MeV proton beam energies and 10–30 μA currents. 68Ga was separated using an automated TRASIS AllinOne synthesizer employing AG 50W-X8 and UTEVA resins. Post-separation recovery of the 68Zn by electrolysis yielded 76.7 ± 4.3%. Radionuclidic purity of cyclotron-produced 68Ga was investigated with gamma spectroscopy using a HPGe-detector. Radiolabeling was investigated using the macrocyclic chelator DOTA and the bombesin-derived peptide NOTA-BBN2. PET imaging was performed using [68Ga]Ga-NOTA-BBN2 in a PC3 xenograft model. 600 μA·min fresh and recycled quadruplet 68Zn target irradiations (n = 8) at 12.5 MeV and 30 μA yielded 13.9 ± 1.0 GBq 68Ga; 2200 μA·min irradiations (n = 3) yielded 37.5 ± 1.9 GBq 68Ga. HPGe analysis showed EOB 0.0074% and 0.0084% of total activity of 66Ga and 67Ga, respectively. Metal impurities were 0.06 ± 0.03 μg/GBq Zn, 0.13 ± 0.007 μg/GBq Fe, and 0.02 ± 0.01 μg/GBq Al for cyclotron 68Ga. Cyclotron and 68Ge/68Ga generator 68Ga respective DOTA and NOTA-BBN2 labeling incorporations were 99.4 ± 0.0% and 99.3 ± 0.2%, and 90.4 ± 1.5% and 93.0 ± 3.6% determined by radio-thin layer chromatography (radio-TLC). Preclinical PET imaging comparison between generator and cyclotron produced 68Ga showed identical radiotracer tumor uptake and biodistribution profiles in PC3 tumor bearing mice. Cyclotron 68Ga production provides highly scalable production with equivalent or superior quality 68Ga to a 68Ge/68Ga generator, while providing identical biodistribution and tumor uptake profiles. Our described targetry is simpler and more cost-effective than existing liquid and solid targetry, enabling a turnkey production system for multi-facility distribution of cyclotron produced 68Ga. The manufacturing simplicity described has potential applications for producing other radiometals such as 44Sc. Our cost-effective method of solid target 68Ga production can enhance 68Ga production capabilities to meet the high demand for 68Ga-radiopharmaceuticals for research and clinical use. [ABSTRACT FROM AUTHOR]

We have developed a nuclear and fluorescence labeling strategy for nanocrystalline cellulose (CNC), an emerging biomaterial with versatile chemistry and facile preparation from renewable sources. We modified CNC through 1,1′-carbonyldiimidazole (CDI) activation with radiometal chelators desferrioxamine B and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), allowing for the labeling with zirconium-89 (t ½ = 78.41 h) and copper-64 (t ½ = 12.70 h), respectively, for non-invasive positron emission tomography (PET) imaging. The far-red fluorescent dye Cy5 was added for ex vivo optical imaging, microscopy and flow cytometry. The multimodal CNC were evaluated in the syngeneic orthotopic 4T1 tumor model of human stage IV breast cancer. Modified CNC exhibited low cytotoxicity in RAW 264.7 macrophages over 96 h, and high radiolabel stability in vitro. After systemic administration, radiolabeled CNC were rapidly sequestered to the organs of the reticulo-endothelial system (RES), indicating immune recognition and no passive tumor targeting by the enhanced permeability and retention (EPR) effect. Modification with NOTA was a more favorable strategy in terms of radiolabeling yield, specific radioactivity, and both the radiolabel and dispersion stability in physiological conditions. Flow cytometry analysis of Cy5-positive immune cells from the spleen and tumor corroborated the uptake of CNC to phagocytic cells. Future studies on the in vivo behavior of CNC should be concentrated on improving the nanomaterial stability and circulation half-life under physiological conditions and optimizing further the labeling yields for the multimodality imaging strategy presented. Our studies constitute one of the first accounts of a multimodality nuclear and fluorescent probe for the evaluation of CNC biodistribution in vivo and outline the pitfalls in radiometal labeling strategies for future evaluation of targeted CNC-based drug delivery systems. Quantitative and sensitive molecular imaging methods provide information on the structure–activity relationships of the nanomaterial and guide the translation from in vitro models to clinically relevant animal models. [ABSTRACT FROM AUTHOR]

• Highly multiplexed SiPM readout scheme via the first-order high-pass filter. • Effectively reducing DAQ channels without severe timing degradation of PET detectors. • Simple and practical readout solution in developing brain-dedicated PET scanners. We investigated the highly multiplexed readout of SiPM signals that are useful in developing brain-dedicated PET detectors wit. DOI-capable crystal blocks and large-area SiPM arrays. The PET detector module used in this study was equipped with a two-layer relative-offset DOI crystal block and a 2 × 2 array of 16-channel SiPMs. The lower crystal-layer consisted of a 14 × 14 array of 1.78 × 1.78 × 8 mm3 LSO crystals and the upper crystal-layer consisted of a 13 × 13 array of 1.78 × 1.78 × 12 mm3 LSO crystals. The energy and position information was obtained via signals from the 8 × 8 resistive charge division multiplexing circuit. The timing performance was evaluated with varying multiplexing ratios (i.e. 16:1, 32:1, and 64:1) via first-order analog high-pass filtering. For three different multiplexing schemes, all LSO crystals with two-layer DOI information were clearly resolved and yielded good energy resolutions of 10.5 ± 1.0% (upper) and 12.1 ± 1.7% (lower). The 16:1 multiplexing yielded an optimal timing performance with average CRT values of 325 ps FWHM (upper) and 342 ps FWHM (lower); however, the timing performances were maintained almost constant even for 64:1 multiplexing with average CRT values of 336 ps FWHM (upper) and 347 ps FWHM (lower). The highly multiplexed SiPM signal readout via the first-order analog high-pass filtering could be an attractive solution to develop brain-dedicated PET scanners, effectively decreasing the burden of DAQ systems with moderate compromise in terms of TOF and DOI performances. [ABSTRACT FROM AUTHOR]

• Use of bioactive fluorine-18 (18F) compounds for positron emission tomography (PET) in medical imaging. • Difluorocarbene-enabled synthesis has been developed as a new approach for making 18F-radiotracers. • Synthesis of 18F-labeled compounds bearing [18F]CF 3 , [18F]SCF 3 , [18F]SeCF 3 , [18F]CF 2 , [18F]SCF 2 , [18F]NCF 2 , and [18F]OCF 2. Positron emission tomography (PET) is a preclinical and clinical imaging technique that is extensively used in biomedical research and disease diagnosis to study and visualize biological and physiological processes. The positron emitter used most frequently for PET imaging is fluorine-18 (18F) due to its practical 109.8 min half-life, high yield production on fragile biomedical cyclotrons, and well-established 18F-radiochemistry. Fluorine atom(s) presented in many drugs and biomarkers that provides the opportunity for the development radioligand-labeled with 18F. Summarized in this paper are difluorocarbene (DFC)-enabled 18F-radiosynthesis to introduce [18F]CF 3 , [18F]CF 2 and related motifs in organic molecules and to use them as bioactive radiotracers. [Display omitted] [ABSTRACT FROM AUTHOR]

Brain positron emission tomography (PET) has several advantages, including improved sensitivity and spatial resolution compared to whole-body PET, which provides a more accurate diagnosis and observation of metabolic activity in the brain. However, the small diameter and design parameter result in a high parallax error and a random count rate, leading to a deteriorated imaging performance. We designed and evaluated brain PET with various design parameters and applied time-of-flight (TOF) technology to overcome the above problems. The aim of the study was to design an optimal structure of the brain dedicated TOF-PET that provides excellent image quality. This study investigated effects of ring diameter, crystal length, and TOF capability on the performance of brain TOF-PET using a Monte-Carlo simulation. Two brain PET were designed and evaluated, consisting of a commercially available brain PET ring diameter (357 mm) and a smaller ring diameter (257 mm) to verify the effect of ring diameter on the performance of the brain PET. Three brain TOF-PET with different crystal thicknesses (10 mm, 15 mm, and 20 mm) and TOF capacities (180 ps, 220 ps, and 260 ps) were assessed and their performances were compared. An optimization study was also performed to design the optimal structure based on the two simulation results. This study determined the optimal structure of brain-dedicated TOF-PET based on trade-offs and performance differences depending on the parameters of brain PET. As a result, we propose a brain-dedicated TOF-PET with a 15 mm crystal length and 257 mm diameter as the optimal structure. The results of this paper could be used to design PET systems for the brain and other specific organs. [ABSTRACT FROM AUTHOR]

Many molecular imaging diagnoses involve comparing two regions of interest (ROIs) in the image or different images. Since the images are obtained by measuring a random phenomenon, such comparisons should be based on a statistical test to ensure reliability. Recent studies have shown that use of the bootstrap approach provides access to the statistical variability of reconstructed values in molecular images. However, although there is general agreement that this increase in information should make diagnosis based on molecular images more reliable, no approach has been proposed in the relevant literature to use bootstrap replicates to enhance the reliability of comparisons of two ROIs. In this paper, we propose to fill this gap by introducing the first statistical test that allows us to compare two sets of pixels/voxels for which bootstrap replicates are available. After presenting the theoretical basis of this non-parametric statistical test, this article describes how to calculate it in practice. Finally, it proposes two experiments based on quantitative comparisons and expert judgment to assess its relevance. The results obtained are consistent with expert diagnosis on synthetic data. This validates the relevance of the D-test. This paper presents the first statistical test to compare two ROIs in reconstructed images for which the statistical variability information is accessible. • Molecular imaging diagnoses involve comparing two regions of interest. • Image reconstruction does not allow direct access to statistical information. • Bootstrap provides access to the statistical variability in reconstructed values. • No statistical test exists to compare two bootstrapped distributions. • D-test proposes a solution to statistically compare regions of interest. [ABSTRACT FROM AUTHOR]

Rapid and complete workup of newly diagnosed esophageal cancer is vital for a timely, individual and high-quality treatment strategy. The aim of this study was to uncover potential delay, inefficiencies and non-contributing investigations in the diagnostic process in two tertiary referral centers. This retrospective cohort study included all newly diagnosed esophageal cancer patients referred to or diagnosed in the Amsterdam UMC and Karolinska University Hospital between July 2020 and July 2021. Radiology, pathological assessment and multidisciplinary team meeting reports were reviewed. To assess time interval from diagnosis to treatment, dates of diagnosis, admittance to referral hospital, MDT meeting and start of treatment were collected. In total, 252 esophageal cancer patients were included, 187 were treated with curative intent. Curatively treated patients had a mean age of 66 years, were predominantly male (74.9 %) with an adenocarcinoma (71.1 %). Curatively treated patients had a median time from diagnosis to referral of seven days (IQR:0–11) and of 35 days (IQR:28–45) between diagnosis and start of treatment. Main reasons for the significant (P < 0.001) differences in time between diagnosis and treatment between centers, Amsterdam UMC (39 days) vs Karolinska (27 days), were need for additional diagnostics (47.8 %) and differences in referral routine. Gastroscopy was repeated in 32.2 % of patients, mainly for further anatomical mapping. Significant time differences between centers in the path from diagnosis to start treatment can be explained by differences in workup approach, referral routines and MDT meeting regulations. Repeat of gastroscopy can be prevented with clearer endoscopy guidelines. • Patients from the Amsterdam UMC had a significantly longer period of time between diagnosis and start of treatment than patients from the Karolinska UH. • Main reason for this difference were need for additional diagnostics and differences in referral routine. • Repeat of gastroscopy during the diagnostic workup can be prevented with clearer guidelines on the information needed from primary gastroscopy. [ABSTRACT FROM AUTHOR]