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Abstract Background The cannabinoid type 2 receptors (CB2R) represent a target of increasing importance in neuroimaging due to its upregulation under various neuropathological conditions. Previous evaluation of [18F]JHU94620 for the non-invasive assessment of the CB2R availability by positron emission tomography (PET) revealed favourable binding properties and brain uptake, however rapid metabolism, and generation of brain-penetrating radiometabolites have been its main limitations. To reduce the bias of CB2R quantification by blood–brain barrier (BBB)-penetrating radiometabolites, we aimed to improve the metabolic stability by developing -d 4 and -d 8 deuterated isotopologues of [18F]JHU94620. Results The deuterated [18F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with K D values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [18F]JHU94620-d 8 in the spleen and to a local hCB2R(D80N) protein overexpression in the striatal region in rats. Conclusion These results support further investigations of [18F]JHU94620-d 8 in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation.

Abstract Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main body This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

Abstract Background Fluorine-18-labeled SSAs have the potential to become the next-generation tracer in SSTR-imaging in neuroendocrine tumor (NET) patients given their logistical advantages over the current gold standard gallium-68-labeled SSAs. In particular, [18F]AlF-OC has already shown excellent clinical performance. We demonstrated in our previous report from our prospective multicenter trial that [18F]AlF-OC PET/CT outperforms [68Ga]Ga-DOTA-SSA, but histological confirmation was lacking due to ethical and practical reasons. In this second arm, we therefore aimed to provide evidence that the vast majority of [18F]AlF-OC PET lesions are in fact true NET lesions by analyzing their MR characteristics on simultaneously acquired MRI. We had a special interest in lesions solely detected by [18F]AlF-OC (“incremental lesions”). Methods Ten patients with a histologically confirmed neuroendocrine tumor (NET) and a standard-of-care [68Ga]Ga-DOTATATE PET/CT, performed within 3 months, were prospectively included. Patients underwent a whole-body PET/MRI (TOF, 3 T, GE Signa), 2 hours after IV injection of 4 MBq/kg [18F]AlF-OC. Positive PET lesions were evaluated for a corresponding lesion on MRI. The diagnostic performance of both PET tracers was evaluated by determining the detection ratio (DR) for each scan and the differential detection ratio (DDR) per patient. Results In total, 195 unique lesions were detected: 167 with [68Ga]Ga-DOTATATE and 193 with [18F]AlF-OC. The DR for [18F]AlF-OC was 99.1% versus 91.4% for [68Ga]Ga-DOTATATE, significant for non-inferiority testing (p = 0.0001). Out of these 193 [18F]AlF-OC lesions, 96.2% were confirmed by MRI to be NET lesions. Thirty-three incremental lesions were identified by [18F]AlF-OC, of which 91% were confirmed by MRI and considered true positives. Conclusion The DR of [18F]AlF-OC was numerically higher and non-inferior to the DR of [68Ga]Ga-DOTATATE. [18F]AlF-OC lesions and especially incremental lesions were confirmed as true positives by MRI in more than 90% of lesions. Taken together, these data further validate [18F]AlF-OC as a new alternative for SSTR PET in clinical practice. Trial registration ClinicalTrials.gov: NCT04552847. Registered 17 September 2020, https://beta.clinicaltrials.gov/study/NCT04552847

Abstract Background Positron emission tomography/computed tomography (PET/CT) using radiotracers that bind to the prostate-specific membrane antigen (PSMA) is mainly used in biochemical recurring prostate cancer. The aim of our study was to assess the usefulness of 18F-JK-PSMA-7 PET/CT for local and nodal staging in patients with intermediate- and high-risk prostate cancer (PCa) prior to radical prostatectomy, as compared to conventional imaging techniques. Methods We enrolled a total of 10 patients with intermediate- and high-risk PCa diagnosed by multiparametric-MRI followed by systematic and targeted biopsies, eligible for radical prostatectomy with extended lymph node dissection. Clinical team was blind to the results of the pre-surgery 18F-JK-PSMA-7 PET/CT at times of clinical decision and surgery. One month post-surgery, 18F-JK-PSMA-7 PET/CT was repeated and the results of both scans were unblinded. A third 18F-JK-PSMA-7 PET/CT could be acquired at a later time point depending on PSA progression. Results All pre-surgery 18F-JK-PSMA-7 PET/CT was positive in the prostatic region, while MRI was negative in the prostate in one patient. We also detected positive pelvic lymph nodes in two patients (one high-risk, one intermediate-risk PCa) on pre-surgery and post-surgery 18F-JK-PSMA-7 PET/CT. No positive pelvic lymph nodes were reported on pre-surgical CT and MRI. 18F-JK-PSMA-7 PET/CT detected bladder involvement in one patient and seminal vesicles involvement in two patients; this malignant extension was undetected by the conventional imaging techniques. SUVmax in prostate lesions had an average value of 11.51 (range 6.90–21.49). SUVmean in prostate lesions had an average value of 7.59 (range 5.26–14.02). Conclusion This pilot study indicates that pre-surgery 18F-JK-PSMA-7 PET/CT provides valuable information in intermediate- and high-risk PCa, for surgery planning with curative intent.

Abstract Background The molecular chaperone, Hsp90, is a key player in the protein quality control system that maintains homeostasis under cellular stress conditions. It is a homodimer with ATP-dependent activity, and is a prominent member of the chaperone machinery that stabilizes, matures and (re)folds an extensive list of client proteins. Hsp90 occurs as four isoforms, cytosolic Hsp90α and Hsp90β, mitochondrial TRAP1 and Grp94 present in the endoplasmic reticulum. An aberrant role of Hsp90 has been attributed to several cancers and neurodegenerative disorders. Consequently, Hsp90 has emerged as an attractive therapeutic target. However, pan-Hsp90 inhibition often leads to detrimental dose-limiting toxicities. Novel strategies for Hsp90-targeted therapy intend to avoid this by using isoform-specific Hsp90 inhibition. In this respect, the radiosynthesis of carbon-11 labeled SNX-ab was developed and [11C]SNX-ab was evaluated as a Hsp90α,β isoform-selective PET probe, which could potentially allow to quantify in vivo Hsp90α,β expression. Results [11C]SNX-ab was synthesized with excellent radiochemical yields of 45% and high radiochemical purity (> 98%). In vitro autoradiography studies on tissue slices of healthy mouse brain, mouse B16.F10 melanoma and U87 glioblastoma using homologous (SNX-ab, SNX-0723) and heterologous (Onalespib and PU-H71) Hsp90 inhibitors demonstrated only limited reduction of tracer binding, indicating that the binding of [11C]SNX-ab was not fully Hsp90-specific. Similarly, [11C]SNX-ab binding to U87 cells was not efficiently inhibited by Hsp90 inhibitors. Ex vivo biodistribution studies in healthy mice revealed limited brain exposure of [11C]SNX-ab and predominantly hepatobiliary clearance, which was confirmed by in vivo full-body dynamic µPET studies. Conclusion Our results suggest that [11C]SNX-ab is not an ideal probe for in vivo visualization and quantification of Hsp90α/β expression levels in tumour and brain. Future research in the development of next-generation Hsp90 isoform-selective PET tracers is warranted to dissect the role played by each isoform towards disease pathology and support the development of subtype-specific Hsp90 therapeutics.

Abstract Rationale [11C]-UCB-J is an emerging tool for the noninvasive measurement of synaptic vesicle density in vivo. Here, we report human biodistribution and dosimetry estimates derived from sequential whole-body PET using two versions of the OLINDA dosimetry program. Methods Sequential whole-body PET scans were performed in 3 healthy subjects for 2 h after injection of 254 ± 77 MBq [11C]-UCB-J. Volumes of interest were drawn over relevant source organs to generate time-activity curves and calculate time-integrated activity coefficients, with effective dose coefficients calculated using OLINDA 2.1 and compared to values derived from OLINDA 1.1 and those recently reported in the literature. Results [11C]-UCB-J administration was safe and showed mixed renal and hepatobiliary clearance, with largest organ absorbed dose coefficients for the urinary bladder wall and small intestine (21.7 and 23.5 μGy/MBq, respectively). The average (±SD) effective dose coefficient was 5.4 ± 0.7 and 5.1 ± 0.8 μSv/MBq for OLINDA versions 1.1 and 2.1 respectively. Doses were lower than previously reported in the literature using either software version. Conclusions A single IV administration of 370 MBq [11C]-UCB-J corresponds to an effective dose of less than 2.0 mSv, enabling multiple PET examinations to be carried out in the same subject. Trial registration EudraCT number: 2016-001190-32. Registered 16 March 2016, no URL available for phase 1 trials.

Abstract Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Results This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

Abstract Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to describe trends in the field. Results This commentary of highlights has resulted in 19 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

Abstract Background Mesenchymal stem cells (MSCs) have shown potential for treatment of different diseases. However, their working mechanism is still unknown. To elucidate this, the non-invasive and longitudinal tracking of MSCs would be beneficial. Both iron oxide-based nanoparticles (Fe3O4 NPs) for magnetic resonance imaging (MRI) and radiotracers for positron emission tomography (PET) have shown potential as in vivo cell imaging agents. However, they are limited by their negative contrast and lack of spatial information as well as short half-life, respectively. In this proof-of-principle study, we evaluated the potential of Fe3O4@Al(OH)3 NPs as dual PET/MRI contrast agents, as they allow stable binding of [18F]F− ions to the NPs and thus, NP visualization and quantification with both imaging modalities. Results 18F-labeled Fe3O4@Al(OH)3 NPs (radiolabeled NPs) or mouse MSCs (mMSCs) labeled with these radiolabeled NPs were intravenously injected in healthy C57Bl/6 mice, and their biodistribution was studied using simultaneous PET/MRI acquisition. While liver uptake of radiolabeled NPs was seen with both PET and MRI, mMSCs uptake in the lungs could only be observed with PET. Even some initial loss of fluoride label did not impair NPs/mMSCs visualization. Furthermore, no negative effects on blood cell populations were seen after injection of either the NPs or mMSCs, indicating good biocompatibility. Conclusion We present the application of novel 18F-labeled Fe3O4@Al(OH)3 NPs as safe cell tracking agents for simultaneous PET/MRI. Combining both modalities allows fast and easy NP and mMSC localization and quantification using PET at early time points, while MRI provides high-resolution, anatomic background information and long-term NP follow-up, hereby overcoming limitations of the individual imaging modalities.

Abstract Background Gallium-68 labeled synthetic somatostatin analogs for PET/CT imaging are the current gold standard for somatostatin receptor imaging in neuroendocrine tumor patients. Despite good imaging properties, their use in clinical practice is hampered by the low production levels of 68Ga eluted from a 68Ge/68Ga generator. In contrast, 18F-tracers can be produced in large quantities allowing centralized production and distribution to distant PET centers. [18F]AlF-NOTA-octreotide is a promising tracer that combines a straightforward Al18F-based production procedure with excellent in vivo pharmacokinetics and specific tumor uptake, demonstrated in SSTR2 positive tumor mice. However, advancing towards clinical studies with [18F]AlF-NOTA-octreotide requires the development of an efficient automated GMP production process and additional preclinical studies are necessary to further evaluate the in vivo properties of [18F]AlF-NOTA-octreotide. In this study, we present the automated GMP production of [18F]AlF-NOTA-octreotide on the Trasis AllinOne® radio-synthesizer platform and quality control of the drug product in accordance with GMP. Further, radiometabolite studies were performed and the pharmacokinetics and biodistribution of [18F]AlF-NOTA-octreotide were assessed in healthy rats using μPET/MR. Results The production process of [18F]AlF-NOTA-octreotide has been validated by three validation production runs and the tracer was obtained with a final batch activity of 10.8 ± 1.3 GBq at end of synthesis with a radiochemical yield of 26.1 ± 3.6% (dc), high radiochemical purity and stability (96.3 ± 0.2% up to 6 h post synthesis) and an apparent molar activity of 160.5 ± 75.3 GBq/μmol. The total synthesis time was 40 ± 3 min. Further, the quality control was successfully implemented using validated analytical procedures. Finally, [18F]AlF-NOTA-octreotide showed high in vivo stability and favorable pharmacokinetics with high and specific accumulation in SSTR2-expressing organs in rats. Conclusion This robust and automated production process provides high batch activity of [18F]AlF-NOTA-octreotide allowing centralized production and shipment of the compound to remote PET centers. Further, the production process and quality control developed for [18F]AlF-NOTA-octreotide is easily implementable in a clinical setting and the tracer is a potential clinical alternative for somatostatin directed 68Ga labeled peptides obviating the need for a 68Ge/68Ga-generator. Finally, the favorable in vivo properties of [18F]AlF-NOTA-octreotide in rats, with high and specific accumulation in SSTR2 expressing organs, supports clinical translation.

Abstract Method Aim of this study was to automatically select a suitable pseudo-reference brain region for the accurate, non-invasive quantification of neuroinflammation in a rat brain using dynamic [18F]DPA-714 PET imaging. Procedures A supervised clustering analysis approach considering three kinetic classes (SVCA3) was used to select an appropriate pseudo-reference brain region. This pseudo-reference region was determined by selecting only brain regions with low specific tracer uptake (SVCA3low) or by taking into account all brain regions and weighting each brain region with the corresponding fraction of low specific binding (SVCA3wlow). Both SVCA3 approaches were evaluated in an animal model of neuro-inflammation induced by lipopolysaccharide injection in the right striatum of female Wistar rats. For this study setup, a population of 25 female Wistar rats received a dynamic PET scan after injection of ~ 60 MBq [18F]DPA-714. Animals were scanned at baseline (n = 3) and at different time points after inducing neuroinflammation: 1 day (n = 3), 3 days (n = 12), 7 days (n = 4), and 30 days (n = 3). Binding potential (BP) values using a simplified reference tissue model (SRTM) and the contralateral striatum as pseudo-reference region were considered as a reference method (BPL STR) and compared with SRTM BP values using a pseudo-reference region obtained by either the SVCA3low or SVCA3wlow approach for both a 90- and 120-min acquisition time interval. Results For the right striatum, SRTM BP values using a SVCA3low- or SVCA3wlow-based pseudo-reference region demonstrated a strong and highly significant correlation with SRTM BPL STR values (Spearman r ≥ 0.89, p

Abstract Background Phosphodiesterase 10A (PDE10A) is an important regulator of nigrostriatal dopamine (DA) neurotransmission. However, little is known on the effect of alterations in DA neurotransmission on PDE10A availability. Here, we used [18F]JNJ42259152 PET to measure changes in PDE10A availability, secondary to pharmacological alterations in DA release and to investigate whether these are D1- or D2-receptor driven. Results Acute treatment of rats using D-amphetamine (5 mg, s.c. and 1 mg/kg i.v.) did not result in a significant change in PDE10A BPND compared to baseline conditions. 5-day D-amphetamine treatment (5 mg/kg, s.c.) increased striatal PDE10A BPND compared to the baseline (+24 %, p = 0.03). Treatment with the selective D2 antagonist SCH23390 (1 mg/kg) and D-amphetamine decreased PDE10A binding (-22 %, p = 0.03). Treatment with only SCH23390 further decreased PDE10A binding (-26 %, p = 0.03). No significant alterations in PDE10A mRNA levels were observed. Conclusions Repeated D-amphetamine treatment significantly increased PDE10A binding, which is not observed upon selective D1 receptor blocking. This study suggests a potential pharmacological interaction between PDE10A enzymes and drugs modifying DA neurotransmission. Therefore, PDE10A binding in patients with neuropsychiatric disorders might be modulated by chronic DA-related treatment.