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[ 18 F]AlF-NOTA-octreotide ([ 18 F]AlF-OC) is a promising alternative for [ 68 Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [ 18 F]AlF-OC PET/CT and [ 68 Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [ 18 F]AlF-OC and [ 68 Ga]Ga-DOTA-TATE or [ 68 Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632-638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [ 68 Ga]Ga-DOTA-SSA or [ 18 F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [ 18 F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [ 68 Ga]Ga-DOTA-SSA, the use of [ 18 F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [ 18 F]AlF-OC. The use of [ 18 F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [ 18 F]AlF-OC PET/CT as an alternative for [ 68 Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15., (© 2024 British Society for Neuroendocrinology.)

We present guidelines by the European Association of Nuclear Medicine (EANM) for routine quality control (QC) of PET-CT and PET-MR systems. These guidelines are partially based on the current EANM guidelines for routine quality control of Nuclear Medicine instrumentation but focus more on the inherent multimodal aspect of the current, state-of-the-art PET-CT and PET-MR scanners. We briefly discuss the regulatory context put forward by the International Electrotechnical Commission (IEC) and European Commission (EC) and consider relevant guidelines and recommendations by other societies and professional organizations. As such, a comprehensive overview of recommended quality control procedures is provided to ensure the optimal operational status of a PET system, integrated with either a CT or MR system. In doing so, we also discuss the rationale of the different tests, advice on the frequency of each test and present the relevant MR and CT tests for an integrated system. In addition, we recommend a scheme of preventive actions to avoid QC tests from drifting out of the predefined range of acceptable performance values such that an optimal performance of the PET system is maintained for routine clinical use., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier GmbH.)

Purpose: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [ 11 C]CHDI-00485180-R ([ 11 C]CHDI-180R) and [ 11 C]CHDI-00485626 ([ 11 C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models., Methods: Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [ 11 C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [ 11 C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1., Results: There were no clinically relevant adverse events. The mean effective dose (ED) for [ 11 C]CHDI-180R was 4.58 ± 0.65 μSv/MBq, with highest absorbed doses for liver (16.9 μGy/MBq), heart wall (15.9 μGy/MBq) and small intestine (15.8 μGy/MBq). Mean ED for [ 11 C]CHDI-626 was 5.09 ± 0.06 μSv/MBq with the highest absorbed doses for the gallbladder (26.5 μGy/MBq), small intestine (20.4 μGy/MBq) and liver (19.6 μGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [ 11 C]CHDI-180R, but for [ 11 C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite., Conclusion: [ 11 C]CHDI-180R and [ 11 C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11 C-ligands. While [ 11 C]CHDI-180R has promising kinetic properties in the brain, [ 11 C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma., Trial Registration: EudraCT number 2020-002129-27., Clinicaltrials: gov NCT05224115 (retrospectively registered)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: PSMA-PET has become the PET technique of choice to localise the site of biochemically recurrent prostate cancer (PCa). With hybrid PET/MRI, the advantages of MRI are added to molecular characteristic of PET. The aim of this study was to investigate the incremental value of PET/MR versus PET/CT in patients with biochemically recurrent PCa by head-to-head comparison., Methods: Thirty-four patients with biochemically recurrent PCa were prospectively included. They underwent [ 68 Ga]Ga-PSMA-11 PET/CT, followed by simultaneous PET/MR. All PET (PET CT , PET MR ), CT and MR images were evaluated for number of lesions and location. The number of lesions at specific sites was compared using Wilcoxon-sign-rank test. For PET, the maximum and mean standardised uptake values (SUVs) were calculated for each lesion compared using a two-sided paired t test., Results: PET CT and PET MR scans were positive in 19 and 20 patients, detecting 73 and 79 lesions respectively. All lesions detected on PET CT were also detected on PET MR . CT and MRI only were positive in 14 and 17 patients, detecting 38 and 50 lesions, respectively, which was significantly lower than PET CT and PET MR respectively. Combined interpretation showed more lesions on PET/MR than on PET/CT (88 vs 81). No significant difference in detection of presence of local recurrence nor distant metastases was found. SUV mean and SUV max values were significantly higher on PET MR than on PET CT in local recurrence and lymph node metastases., Conclusions: [ 68 Ga]Ga-PSMA-11 PET/MR was able to detect biochemically recurrent PCa at least as accurately as PET/CT for local recurrence, lymph node metastasis and distant metastasis., Key Points: • PSMA PET/MRI detects the location of biochemical recurrence at least as accurately as PET/CT. • Substitution of PET/CT by PET/MRI adds sensitivity in PSMA lesion detection also in the setting of distant recurrence due to both the MR and TOF PET components., (© 2021. European Society of Radiology.)

Purpose: To evaluate the prognostic utility of apparent diffusion coefficient (ADC) changes at whole-body diffusion-weighted (WB-DW) MRI after one treatment cycle for aggressive non-Hodgkin lymphoma (NHL) compared with response assessment at interim and end-of-treatment fluorine 18 ( 18 F) fluorodeoxyglucose (FDG) PET/CT., Materials and Methods: This was a secondary analysis of a prospective study (ClinicalTrials.gov identifier: NCT01231269) in which participants with aggressive NHL were recruited between March 2011 and April 2015 and underwent WB-DW MRI before and after one cycle of immunochemotherapy. Volunteers were recruited for test-retest WB-DW MRI (ClinicalTrials.gov identifier: NCT01231282) to assess ADC measurement repeatability. Response assessment was based on ADC change after one treatment cycle at WB-DW MRI and Deauville criteria at 18 F-FDG PET/CT. To evaluate prognostic factors of disease-free survival (DFS), Kaplan-Meier survival analysis and univariable and multivariable Cox regression were performed; intraclass correlation coefficient (ICC) and mean difference with limits of agreement were calculated to determine inter- and intraobserver repeatability of ADC measurements., Results: Forty-five patients (mean age, 58 years ± 17 [standard deviation]; 31 men) and nine volunteers (mean age, 22 years ± 3; seven men) were enrolled. Median DFS was 48 months (range, 2-48 months). Outcome prediction accuracy was 86.7% (39 of 45), 71.4% (30 of 42), and 73.8% (31 of 42) for WB-DW MRI and interim and end-of-treatment 18 F-FDG PET/CT, respectively. WB-DW MRI (hazard ratio [HR], 17.8; P < .001) and interim (HR, 5; P = .008) and end-of-treatment (HR, 4.3; P = .017) 18 F-FDG PET/CT were prognostic of DFS. After multivariable analysis, WB-DW MRI remained an independent predictor of outcome (HR, 26.8; P = .002). Intra- and interobserver agreement for ADC measurements were excellent (ICC = 0.85-0.99)., Conclusion: Quantitative WB-DW MRI after only one cycle of immunochemotherapy predicts DFS in aggressive NHL and is noninferior to routinely performed interim and end-of-treatment 18 F-FDG PET/CT. Keywords: MR-Diffusion Weighted Imaging, Lymphoma, Oncology, Tumor Response, Whole-Body Imaging Supplemental material is available for this article. © RSNA, 2021., Competing Interests: Disclosures of Conflicts of Interest: K.N.D.P. disclosed no relevant relationships. C.A.V.K. disclosed no relevant relationships. G.M.A. disclosed no relevant relationships. F.D.K. disclosed no relevant relationships. O.G. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: author received consultancy fees from IBA and payment for lectures including service on speakers bureaus from Pfizer. Other relationships: disclosed no relevant relationships. O.B. disclosed no relevant relationships. P.W. disclosed no relevant relationships. D.D. disclosed no relevant relationships. A.J. disclosed no relevant relationships. G.V. disclosed no relevant relationships. R.O. disclosed no relevant relationships. M.K. disclosed no relevant relationships. V.V. disclosed no relevant relationships., (2021 by the Radiological Society of North America, Inc.)

Purpose: Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer's disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [ 18 F]EKZ-001 ([ 18 F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects., Methods: Biodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT. The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-min dynamic PET/MR scans using a radiometabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a 1-day interscan interval to determine test-retest variability (TRV). Regional volume of distribution (V T ) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. V T differences between males and females were evaluated using volume of interest and whole-brain voxel-wise approaches., Results: The effective dose was 39.1 ± 7.0 μSv/MBq. Based on the Akaike information criterion, 2TCM was the preferred model compared to 1TCM. Regional LGA V T were in agreement with 2TCM V T , however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional V T values were relatively homogeneous with highest values in the hippocampus and entorhinal cortex. Reduction of acquisition time was achieved with a 0 to 60-min scan followed by a 90 to 120-min scan. Males demonstrated significantly higher V T than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported., Conclusion: [ 18 F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with Logan graphical analysis as the preferred quantitative approach. Males showed higher HDAC6 expression across the brain compared to females.

We performed post hoc analyses on the utility of pretherapeutic and early interim 68 Ga-DOTATOC PET tumor uptake and volumetric parameters and a recently proposed biomarker, the inflammation-based index (IBI), for peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumor (NET) patients treated with 90 Y-DOTATOC in the setting of a prospective phase II trial. Methods: Forty-three NET patients received up to 4 cycles of 90 Y-DOTATOC at 1.85 GBq/m 2 /cycle with a maximal kidney biologic effective dose of 37 Gy. All patients underwent 68 Ga-DOTATOC PET/CT at baseline and 7 wk after the first PRRT cycle. 68 Ga-DOTATOC-avid tumor lesions were semiautomatically delineated using a customized SUV threshold-based approach. PRRT response was assessed on CT using RECIST 1.1. Results: Median progression-free survival and overall survival (OS) were 13.9 and 22.3 mo, respectively. An SUV mean higher than 13.7 (75th percentile) was associated with better survival (hazard ratio [HR], 0.45; P = 0.024), whereas a 68 Ga-DOTATOC-avid tumor volume higher than 578 cm 3 (75th percentile) was associated with worse OS (HR, 2.18; P = 0.037). Elevated baseline IBI was associated with worse OS (HR, 3.90; P = 0.001). Multivariate analysis corroborated independent associations between OS and SUV mean ( P = 0.016) and IBI ( P = 0.015). No significant correlations with progression-free survival were found. A composite score based on SUV mean and IBI allowed us to further stratify patients into 3 categories with significantly different survival. On early interim PET, a decrease in SUV mean of more than 17% (75th percentile) was associated with worse survival (HR, 2.29; P = 0.024). Conclusion: Normal baseline IBI and high 68 Ga-DOTATOC tumor uptake predict better outcome in NET patients treated with 90 Y-DOTATOC. This method can be used for treatment personalization. Interim 68 Ga-DOTATOC PET does not provide information for treatment personalization., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: [ 18 F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [ 18 F]MK-6240 for its potential application in human brain imaging studies., Procedures: MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 μg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [ 18 F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose)., Results: MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 μg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 μg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [ 18 F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 μGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 μSv/MBq, which is in the typical range for F-18 radiolabeled ligands., Conclusions: Microdoses of [ 18 F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [ 18 F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year.

Purpose: The P2X7 receptor (P2X7R) is an ATP-gated ion channel predominantly expressed on activated microglia and is important in neurodegenerative diseases including Parkinson's disease (PD). In this first-in-human study, we investigated [ 11 C]JNJ54173717 ([ 11 C]JNJ717), a selective P2X7R tracer, in healthy volunteers (HV) and PD patients. Biodistribution, dosimetry, kinetic modelling and short-term test-retest variation (TRV), as well as possible genotype effects, were investigated., Methods: Biodistribution and radiation dosimetry studies were performed in three HV (mean age 30 ± 2 years, two women) using whole-body PET/CT. The most appropriate kinetic model was determined in 11 HV (mean age 62 ± 10 years, six women) and 10 PD patients (mean age 64 ± 8 years, three women; mean UPDRS motor score 21 ± 8) using 90-min dynamic simultaneous PET/MR scans. The total volume of distribution (V T ) was calculated using a one-tissue and a two-tissue compartment model (1TCM, 2TCM) and Logan graphical analysis, and its time stability was assessed. Seven subjects underwent retest scans (mean age 60 ± 13 years, four HV, one woman). A group analysis was performed to compare PD patients and HV. Finally, 13 exons of P2X7R were genotyped in all subjects included in the second part of the study., Results: The mean effective dose was 4.47 ± 0.32 μSv/MBq, with the highest absorbed doses to the gallbladder, liver and small intestine. A reversible 2TCM was the most appropriate kinetic model with relatively homogeneous V T values in the grey and white matter. Average V T values were 3.4 ± 0.8 in HV and 3.3 ± 0.7 in PD patients, with no significant difference between the groups, but a possible genotype effect (rs3751143) was identified which can affect V T . Average TRV was 10-15%. The stability of V T over time allowed a reduction in scan time to 70 min., Conclusion: [ 11 C]JNJ717 is safe and suitable for quantifying P2X7R expression in human brain. In this pilot study, no significant differences in P2X7R binding were found between HV and PD patients. The results also suggest that genotype effects need to be incorporated in future P2X7R PET analyses.

Ubiquicidin is an antimicrobial peptide with great potential for nuclear imaging of infectious diseases, as its cationic-rich fragment TGRAKRRMQYNRR (UBI) has been functionalized with NOTA to allow complexation to 68 Ga ( 68 Ga-NOTA-UBI). We herein assess the cytotoxicity and radiation dosimetry for 68 Ga-NOTA-UBI and a first-in-human evaluation to diagnose infectious processes. Methods: Cytotoxicity was evaluated in green monkey kidney epithelial (Vero) cells and MT-4 leukocytes. Tracer susceptibility was studied in vitro using different bacterial and fungal strains. PET/CT-based biodistribution, pharmacokinetics, and radiation dosimetry were performed on nonhuman primates. Two healthy volunteers and 3 patients with suspected infection underwent 68 Ga-NOTA-UBI PET/CT imaging. Results: Negligible cytotoxicity was determined for NOTA-UBI. 68 Ga-NOTA-UBI showed moderate blood clearance (29-min half-life) and predominant renal clearance in nonhuman primates. Human radiation dose estimates indicated the bladder wall as the dose-critical tissue (185 μSv/MBq), followed by the kidneys (23 μSv/MBq). The total absorbed body dose was low (<7 μSv/MBq); the effective dose was estimated at 17 μSv/MBq. 68 Ga-NOTA-UBI could diagnose bone- and soft-tissue infection in 3 of 3 patients. Conclusion: 68 Ga-NOTA-UBI is considered a nontoxic, safe-to-administer radiopharmaceutical unlikely to cause adverse effects in humans. The favorable tracer biodistribution and the first-in-human results will make 68 Ga-NOTA-UBI PET/CT an encouraging future diagnostic technique with auxiliary clinical relevance., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To investigate the relationship between the dynamic parameters (Ki) and static image-derived parameters of 68Ga-DOTATOC-PET, to determine which static parameter best reflects underlying somatostatin-receptor-expression (SSR) levels on neuroendocrine tumours (NETs)., Patients, Methods: 20 patients with metastasized NETs underwent a dynamic and static 68Ga-DOTATOC-PET before PRRT and at 7 and 40 weeks after the first administration of 90Y-DOTATOC (in total 4 cycles were planned); 175 lesions were defined and analyzed on the dynamic as well as static scans. Quantitative analysis was performed using the software PMOD. One to five target lesions per patient were chosen and delineated manually on the baseline dynamic scan and further, on the corresponding static 68Ga-DOTATOC-PET and the dynamic and static 68Ga-DOTATOC-PET at the other time-points; SUVmax and SUVmean of the lesions was assessed on the other six scans. The input function was retrieved from the abdominal aorta on the images. Further on, Ki was calculated using the Patlak-Plot. At last, 5 reference regions for normalization of SUVtumour were delineated on the static scans resulting in 5 ratios (SUVratio)., Results: SUVmax and SUVmean of the tumoural lesions on the dynamic 68Ga-DOTATOC-PET had a very strong correlation with the corresponding parameters in the static scan (R²: 0.94 and 0.95 respectively). SUVmax, SUVmean and Ki of the lesions showed a good linear correlation; the SUVratios correlated poorly with Ki. A significantly better correlation was noticed between Ki and SUVtumour(max and mean) (p < 0.0001)., Conclusions: As the dynamic parameter Ki correlates best with the absolute SUVtumour, SUVtumour best reflects underlying SSR-levels in NETs.