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Objective: Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects.Method: Images of mGluR5 receptor binding were acquired using PET with [(11)C]ABP688, which binds to an allosteric site with high specificity, in 11 unmedicated individuals with major depression and 11 matched healthy comparison subjects. The amount of mGluR5 protein was investigated using Western blot in postmortem brain samples of 15 depressed individuals and 15 matched comparison subjects.Results: The PET study revealed lower levels of regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus, and the hippocampus in the depression group relative to the comparison group. Severity of depression was negatively correlated with mGluR5 binding in the hippocampus. The postmortem study showed lower levels of mGluR5 protein expression in the prefrontal cortex (Brodmann's area 10) in the depression group relative to the comparison group, while prefrontal mGluR1 protein expression did not differ between groups.Conclusions: The lower levels of mGluR5 binding observed in the depression group are consonant with the lower levels of protein expression in brain tissue in the postmortem depression group. Thus, both studies suggest that basal or compensatory changes in excitatory neurotransmission play roles in the pathophysiology of major depression. [ABSTRACT FROM AUTHOR]

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs. The pursuit of new therapeutic agents has been enhanced by the creation of specialized labeled chemical probes, which aid in target localization, mechanistic studies, assay development, and the establishment of biomarkers for target engagement. By fusing medicinal chemistry with chemical biology in a comprehensive, translational end-to-end drug discovery strategy, we have expedited the development of novel therapeutics. Additionally, this strategy promises to foster highly productive partnerships between industry and academia, as will be illustrated through various examples., (Copyright 2024 Johannes Aebi, Kenneth Atz, Simon M. Ametamey, Jörg Benz, Julie Blaising, Stefania Butini, Giuseppe Campiani, Erick M. Carreira, Ludovic Collin, Eva de Lago, Thais Gazzi, Jürg Gertsch, Luca Gobbi, Wolfgang Guba, Javier Fernández-Ruiz, Jürgen Fingerle, Ahmed Haider, Yingfang He, Laura H. Heitman, Michael Honer, Daniel Hunziker, Bernd Kuhn, Mauro Maccarrone, Hans Peter Märki, Rainer E. Martin, Peter Mohr, Linjing Mu, Marc Nazaré, David F. Nippa, Sergio Oddi, Fionn O’Hara, Pal Pacher, Julian Romero, Stephan Röver, Arne C. Rufer, Roger Schibli, Gisbert Schneider, Antonia F. Stepan, David A. Sykes, Christoph Ullmer, Mario van der Stelt, Dmitry B. Veprintsev, Matthias B. Wittwer, Uwe Grether. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes. Overexpression of MTMR7 reduced RAS GTPase activities and protein levels, ERK1/2 phosphorylation, c-FOS transcription and cancer cell proliferation in vitro. We located the RAS-inhibitory activity of MTMR7 to its charged coiled coil (CC) region and demonstrate direct interaction with the gastrointestinal cancer-relevant K-RAS G12V mutant, favouring its GDP-bound state. In mouse models of gastric and intestinal cancer, a cell-permeable MTMR7-CC mimicry peptide decreased tumour growth, Ki67 proliferation index and ERK1/2 nuclear positivity. Thus, MTMR7 mimicry peptide(s) could provide a novel strategy for targeting mutant K-RAS in cancers., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The N -methyl-d-aspartate receptor (NMDAR) subtype 2B (GluN1/2B) is implicated in various neuropathologies. Given the lack of a validated radiofluorinated positron emission tomography (PET) probe for the imaging of GluN1/2B receptors, we comprehensively investigated the enantiomers of [ 18 F]OF-NB1 in rodents. Particularly, the ( R )- and ( S )- enantiomers were evaluated using in silico docking, in vitro autoradiography, in vivo PET imaging, and ex vivo biodistribution studies. A select panel of GluN1/2B antagonists (CP-101,606, CERC-301, and eliprodil) and the off-target sigma-1 receptor ligands (fluspidine and SA4503) were used to determine the specificity and selectivity of the tested enantiomers. Additionally, a nonmetal-mediated radiofluorination strategy was devised that harnesses the potential of diaryliodoniums in the nucleophilic radiofluorination of nonactivated aromatic compounds. Both enantiomers exhibited known GluN1/2B binding patterns; however, the R -enantiomer showed higher GluN1/2B-specific accumulation in rodent autoradiography and higher brain uptake in PET imaging experiments compared to the S -enantiomer. Molecular simulation studies provided further insights with respect to the difference in binding, whereby a reduced ligand-receptor interaction was observed for the S -enantiomer. Nonetheless, both enantiomers showed dose dependency when two different doses (1 and 5 mg/kg) of the GluN1/2B antagonist, CP-101,606, were used in the PET imaging study. Taken together, ( R )-[ 18 F]OF-NB1 appears to exhibit the characteristics of a suitable PET probe for imaging of GluN2B-containing NMDARs in clinical studies.

GluN2B subunit-containing N- methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. The aim of this study was to develop a novel synthetic approach that allows an enantiomerically pure radiosynthesis of the previously reported PET radioligands ( R ) - [ 18 F]OF-NB1 and ( S ) - [ 18 F]OF-NB1 as well as to assess their in vitro and in vivo performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents. A novel synthetic approach was successfully developed, which allows for the enantiomerically pure radiosynthesis of ( R ) - [ 18 F]OF-NB1 and ( S ) - [ 18 F]OF-NB1 and the translation of the probe to the clinic. While both enantiomers were selective over sigma2 receptors in vitro and in vivo , ( R ) - [ 18 F]OF-NB1 showed superior GluN2B subunit specificity by in vitro autoradiography and higher volumes of distribution in the rodent brain by small animal PET studies.

N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson's, Alzheimer's, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications. Here, we identified (R)-OF-NB1 as a promising splice variant selective NMDAR antagonist. We investigated the interaction of (R)-OF-NB1 and NMDAR from a biochemical, bioinformatical, and electrophysiological perspective to characterize the downstream allosteric modulation of NMDAR by 3-benzazepine derivatives. The allosteric modulatory pathway starts at the ifenprodil binding pocket in the amino terminal domain and immobilizes the connecting α5-helix to the ligand binding domain, resulting in inhibition. In contrast, the exon 5 splice variant GluN1-1b elevates the NMDARs flexibility and promotes the open state of its ligand binding domain., (© 2023. The Author(s).)

Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N = 103; 69 recreational CU and 34 dependent CU) and stimulant-naïve healthy controls (N = 92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N = 33; controls: N = 43). In an additional analysis using 11 C-ABP688 positron emission tomography (PET) in a male subsample (CU: N = 18; controls: N = 16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence., (© 2023. Springer Nature Limited.)

The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [ 18 F]RoSMA-18-d 6 , which proved to be highly suitable for in vitro and in vivo mapping of CB2 in rodents. The aim of this study was to assess the performance characteristics of [ 18 F]RoSMA-18-d 6 in nonhuman primates (NHPs) to pave the way for clinical translation. [ 18 F]RoSMA-18-d 6 was synthesized from the respective tosylate precursor according to previously reported procedures. In vitro autoradiograms with NHP spleen tissue sections revealed a high binding of [ 18 F]RoSMA-18-d 6 to the CB2-rich NHP spleen, which was significantly blocked by coincubation with the commercially available CB2 ligand, GW405833 (10 μM). In contrast, no specific binding was observed by in vitro autoradiography with NHP brain sections, which was in agreement with the notion of a CB2-deficient healthy mammalian brain. In vitro findings were corroborated by PET imaging experiments in NHPs, where [ 18 F]RoSMA-18-d 6 uptake in the spleen was dose-dependently attenuated with 1 and 5 mg/kg GW405833, while no specific brain signal was observed. Remarkably, we observed tracer uptake and retention in the NHP spinal cord, which was reduced by GW405833 blockade, pointing toward a potential utility of [ 18 F]RoSMA-18-d 6 in probing CB2-expressing cells in the bone marrow. If these observations are substantiated in NHP models of enhanced leukocyte proliferation in the bone marrow, [ 18 F]RoSMA-18-d 6 may serve as a valuable marker for hematopoietic activity in various pathologies. In conclusion, [ 18 F]RoSMA-18-d 6 proved to be a suitable PET radioligand for imaging CB2 in NHPs, supporting its translation to humans.

Background: Myocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. 18 F-flurpiridaz was recently introduced as a valid alternative to currently used PET-MPI probes. Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with 18 F-flurpiridaz is feasible in mice., Methods: Rest/stress PET-MPI was performed with 18 F-flurpiridaz (0.6-3.0 MBq) in 27 mice aged 7-8 months. Regadenoson (0.1 µg/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial 18 F-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium., Results: Tracer kinetics were best described by a two-tissue compartment model. K 1 ranged from 6.7 to 20.0 mL·cm -3 ·min -1 , while myocardial volumes of distribution (V T ) were between 34.6 and 83.6 mL·cm -3 . Of note, myocardial 18 F-flurpiridaz uptake (%ID/g) was significantly correlated with K 1 at rest and following pharmacological vasodilation for all time intervals assessed. However, while Spearman's coefficients (r s ) ranged between 0.478 and 0.681, R 2 values were generally low. In contrast, an excellent correlation of myocardial 18 F-flurpiridaz uptake with V T was obtained, particularly when employing the averaged myocardial uptake from 20 to 40 min post tracer injection (R 2 ≥ 0.98). Notably, K 1 and V T were similarly sensitive to pharmacological vasodilation induction. Further, mean stress-to-rest ratios of K 1 , V T , and %ID/g 18 F-flurpiridaz were virtually identical, suggesting that %ID/g 18 F-flurpiridaz can be used to estimate coronary flow reserve (CFR) in mice., Conclusion: Our findings suggest that a simplified assessment of relative myocardial perfusion and CFR, based on image-derived tracer uptake, is feasible with 18 F-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents., (© 2022. The Author(s).)

Despite 2 decades of research, no N -methyl-d-aspartate (NMDA) glutamate receptor (GluN) subtype 2B (GluN1/2B) radioligand is yet clinically validated. Previously, we reported on ( rac )- 18 F-OF-NB1 as a promising GluN1/2B PET probe in rodents and its successful application for the visualization of GluN2B-containing NMDA receptors in postmortem brain tissues of patients with amyotrophic lateral sclerosis. In the current work, we report on the in vivo characterization of ( rac )-, ( R )-, and ( S )- 18 F-OF-NB1 in nonhuman primates. Methods: PET scans were performed on rhesus monkeys. Plasma profiling was used to obtain the arterial input function. Regional brain time-activity curves were generated and fitted with the 1- and 2-tissue-compartment models and the multilinear analysis 1 method, and the corresponding regional volumes of distribution were calculated. Blocking studies with the GluN1/2B ligand Co 101244 (0.25 mg/kg) were performed for the enantiopure radiotracers. Receptor occupancy, nonspecific volume of distribution, and regional binding potential ( BP ND ) were obtained. Potential off-target binding toward σ 1 receptors was assessed for ( S )- 18 F-OF-NB1 using the σ 1 receptor ligand FTC-146. Results: Free plasma fraction was moderate, ranging from 12% to 16%. All radiotracers showed high and heterogeneous brain uptake, with the highest levels in the cortex. ( R )- 18 F-OF-NB1 showed the highest uptake and slowest washout kinetics of all tracers. The 1-tissue-compartment model and multilinear analysis 1 method fitted the regional time-activity curves well for all tracers and produced reliable regional volumes of distribution, which were higher for ( R )- than ( S )- 18 F-OF-NB1. Receptor occupancy by Co 101244 was 85% and 96% for ( S )- 18 F-OF-NB1 and ( R )- 18 F-OF-NB1, respectively. Pretreatment with FTC-146 at both a low (0.027 mg/kg) and high (0.125 mg/kg) dose led to a similar reduction (48% and 49%, respectively) in specific binding of ( S )- 18 F-OF-NB1. Further, pretreatment with both Co 101244 and FTC-146 did not result in a further reduction in specific binding compared with Co 101244 alone in the same monkey (82% vs. 81%, respectively). Regional BP ND values ranged from 1.3 in the semiovale to 3.4 in the cingulate cortex for ( S )- 18 F-OF-NB1. Conclusion: Both ( R )- and ( S )- 18 F-OF-NB1 exhibited high binding specificity to GluN2B subunit-containing NMDA receptors. The fast washout kinetics, good regional BP ND values, and high plasma free fraction render ( S )- 18 F-OF-NB1 an attractive radiotracer for clinical translation., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Stroke is one of the most prevalent vascular diseases. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptor (CB 2 R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [ 18 F]RoSMA-18-d6 and structural imaging by magnetic resonance imaging (MRI)., Procedures: Our recently developed CB 2 R PET tracer [ 18 F]RoSMA-18-d6 was used for imaging neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB 2 R and other inflammatory markers were analyzed by quantitative real-time polymerase chain reaction using brain tissues from tMCAO (1 h occlusion) and sham-operated mice. [ 18 F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging and T 2 -weighted imaging were performed for anatomical reference and delineating the lesion in tMCAO mice., Results: mRNA expressions of inflammatory markers TNF-α, Iba1, MMP9 and GFAP, CNR2 were increased to 1.3-2.5 fold at 24 h after reperfusion in the ipsilateral compared to contralateral hemisphere of tMCAO mice, while mRNA expression of the neuronal marker MAP-2 was markedly reduced to ca. 50 %. Reduced [ 18 F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [ 18 F]RoSMA-18-d6 in ex vivo biodistribution studies and higher standard uptake value ratio (SUVR) were detected in the ischemic ipsilateral compared to contralateral striatum in tMCAO mice, the in vivo specificity of [ 18 F]RoSMA-18-d6 was confirmed only in the CB 2 R-rich spleen., Conclusions: This study revealed an increased [ 18 F]RoSMA-18-d6 measure of CB 2 R and a reduced [ 18 F]FDG measure of CMRglc in the ischemic striatum of tMCAO mice at subacute stage. [ 18 F]RoSMA-18-d6 might be a promising PET tracer for detecting CB 2 R alterations in animal models of neuroinflammation without neuronal loss., (© 2021. The Author(s).)

Neuroinflammation plays an important role in the pathophysiology of Alzheimer's disease. The cannabinoid type 2 receptor (CB 2 R) is an emerging target for neuroinflammation and therapeutics of Alzheimer's disease. Here, we aim to assess the alterations in brain CB 2 R levels and evaluate novel CB 2 R imaging tracers in the arcAß mouse model of Alzheimer's disease amyloidosis. Immunohistochemical staining for amyloid-ß deposits (6E10), microgliosis (anti-Iba1 and anti-CD68 antibodies), astrocytes (GFAP) and the anti-CB 2 R antibody was performed on brain slices from 17-month-old arcAß mice. Autoradiography using the CB 2 R imaging probes [ 18 F]RoSMA-18-d6, [ 11 C]RSR-056, and [ 11 C]RS-028 and mRNA analysis were performed in brain tissue from arcAß and non-transgenic littermate (NTL) mice at 6, 17, and 24 months of age. Specific increased CB 2 R immunofluorescence intensities on the increased number of GFAP-positive astrocytes and Iba1-positive microglia were detected in the hippocampus and cortex of 17-month-old arcAß mice compared to NTL mice. CB 2 R immunofluorescence was higher in glial cells inside 6E10-positive amyloid-ß deposits than peri-plaque glial cells, which showed low background immunofluorescence in the hippocampus and cortex of 17-month-old arcAß mice. Ex vivo autoradiography showed that the specific binding of [ 18 F]RoSMA-18-d6 and [ 11 C]RSR-056 was comparable in arcAß and NTL mice at 6, 17, and 24 months of age. The level of Cnr2 mRNA expression in the brain was not significantly different between arcAß and NTL mice at 6, 17, or 24 months of age. In conclusion, we demonstrated pronounced specific increases in microglial and astroglial CB 2 R expression levels in a mouse model of AD-related cerebral amyloidosis, emphasizing CB 2 R as a suitable target for imaging neuroinflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kecheliev, Spinelli, Herde, Haider, Mu, Klohs, Ametamey and Ni.)

Background: The NMDA receptor (NMDAR) plays a key role in the central nervous system, e.g., for synaptic transmission. While synaptic NMDARs are thought to have protective characteristics, activation of extrasynaptic NMDARs might trigger excitotoxic processes linked to neuropsychiatric disorders. Since extrasynaptic NMDARs are typically GluN2B-enriched, the subunit is an interesting target for drug development and treatment monitoring. Recently, the novel GluN2B-specific PET radioligand (R)-[ 11 C]Me-NB1 was investigated in rodents and for the first time successfully translated to humans. To assess whether (R)-[ 11 C]Me-NB1 is a valuable radioligand for (repeated) clinical applications, we evaluated its safety, biodistribution and dosimetry., Methods: Four healthy subjects (two females, two males) underwent one whole-body PET/MR measurement lasting for more than 120 min. The GluN2B-specific radioligand (R)-[ 11 C]Me-NB1 was administered simultaneously with the PET start. Subjects were measured in nine passes and six bed positions from head to mid-thigh. Regions of interest was anatomically defined for the brain, thyroid, lungs, heart wall, spleen, stomach contents, pancreas, liver, kidneys, bone marrow and urinary bladder contents, using both PET and MR images. Time-integrated activity coefficients were estimated to calculate organ equivalent dose coefficients and the effective dose coefficient. Additionally, standardized uptake values (SUV) were computed to visualize the biodistribution., Results: Administration of the radioligand was safe without adverse events. The organs with the highest uptake were the urinary bladder, spleen and pancreas. Organ equivalent dose coefficients were higher in female in almost all organs, except for the urinary bladder of male. The effective dose coefficient was 6.0 µSv/MBq., Conclusion: The GluN2B-specific radioligand (R)-[ 11 C]Me-NB1 was well-tolerated without reported side effects. Effective dose was estimated to 1.8 mSv when using 300 MBq of presented radioligand. The critical organ was the urinary bladder. Due to the low effective dose coefficient of this radioligand, longitudinal studies for drug development and treatment monitoring of neuropsychiatric disorders including neurodegenerative diseases are possible. Trial registration Registered on 11th of June 2019 at https://www.basg.gv.at (EudraCT: 2018-002933-39)., (© 2022. The Author(s).)

GluN2B-enriched N -methyl-D-aspartate receptors (NMDARs) are implicated in several neurodegenerative and psychiatric diseases, such as Alzheimer's disease. No clinically valid GluN1/2B therapeutic exists due to a lack of selective GluN2B imaging tools, and the state-of-the-art [ 3 H]ifenprodil shows poor selectivity in drug screening. To this end, we developed a tritium-labeled form of OF-NB1, a recently reported selective GluN1/2B positron emission tomography imaging (PET) agent, with a molar activity of 1.79 GBq/µmol. The performance of [ 3 H]OF-NB1 and [ 3 H]ifenprodil was compared through head-to-head competitive binding experiments, using the GluN1/2B ligand CP-101,606 and the sigma-1 receptor (σ1R) ligand SA-4503. Contrary to [ 3 H]ifenprodil, the usage of [ 3 H]OF-NB1 differentiated between GluN1/2B and σ1R binding components. These results were corroborated by observations from PET imaging experiments in Wistar rats using the σ1R radioligand [ 18 F]fluspidine. To unravel the binding modes of OF-NB1 and ifenprodil in GluN1/2B and σ1Rs, we performed a retrospective in silico study using a molecular operating environment. OF-NB1 maintained similar interactions to GluN1/2B as ifenprodil, but only ifenprodil successfully fitted in the σ1R pocket, thereby explaining the high GluN1/2B selectivity of OF-NB1 compared to ifenprodil. We successfully showed in a proof-of-concept study the superiority of [ 3 H]OF-NB1 over the gold standard [ 3 H]ifenprodil in the screening of potential GluN1/2B drug candidates.

The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability in vivo . Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: (R) -[ 11 C]NR2B-Me, (R) -[ 18 F]OF-Me-NB1, and (S) -[ 18 F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques. Free fraction in plasma was <2% for (R) -[ 11 C]NR2B-Me and (R) -[ 18 F]OF-Me-NB1 and higher for (S) -[ 18 F]OF-NB1 (15%). All radiotracers showed good brain uptake and distribution throughout grey matter, with substantial (>68%) blockade across the brain by the GluN2B-targeting drug Co-101,244 (0.25 mg/kg), including in the cerebellum. Time-activity curves were well-fitted by the one-tissue compartment model, with volume of distribution values of 20-40 mL/cm 3 for (R) -[ 11 C]NR2B-Me, 8-16 mL/cm 3 for (R) -[ 18 F]OF-Me-NB1, and 15-35 mL/cm 3 for (S) -[ 18 F]OF-NB1. Estimates of regional non-displaceable binding potential were in the range of 2-3 for (R) -[ 11 C]NR2B-Me and (S) -[ 18 F]-OF-NB1, and 0.5-1 for (R) -[ 18 F]OF-Me-NB1. Altogether, each radiotracer showed an acceptable profile for quantitative imaging of GluN2B. (S) -[ 18 F]OF-NB1 has particularly promising imaging characteristics for potential translation into humans. However, the source of unexpected displaceable binding in the cerebellum for each of these compounds requires further investigation.

Background: A growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR., Methods: Rest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [ 18 F]flurpiridaz in a total of 56 mice (7-8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [ 18 F]flurpiridaz uptake (% injected dose per mL, % ID/mL) was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFR App ) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging., Results: Orchiectomy resulted in a significant decrease of resting myocardial perfusion (Gx vs. sham, 19.4 ± 1.0 vs. 22.2 ± 0.7 % ID/mL, p = 0.034), while myocardial perfusion at stress remained unchanged (Gx vs. sham, 27.5 ± 1.2 vs. 27.3 ± 1.2 % ID/mL, p = 0.896). Accordingly, CFR App was substantially higher in orchiectomized males (Gx vs. sham, 1.43 ± 0.04 vs. 1.23 ± 0.05, p = 0.004), and low serum testosterone levels were linked to a blunted resting myocardial perfusion (r = 0.438, p = 0.020) as well as an enhanced CFR App (r = -0.500, p = 0.007). In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females., Conclusion: Our experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients., (© 2022. The Author(s).)

The N -methyl-d-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer disease and in the treatment of major depression by fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of interest as diagnostic and therapeutic targets. Recently, ( R )- 11 C-Me-NB1 was investigated preclinically and shown to be a promising radioligand for imaging GluN2B subunits. Here, we report on the performance characteristics of this radioligand in a first-in-humans PET study. Methods: Six healthy male subjects were scanned twice on a fully integrated PET/MR scanner with ( R )- 11 C-Me-NB1 for 120 min. Brain uptake and tracer distribution over time were investigated by SUVs. Test-retest reliability was assessed with the absolute percentage difference and the coefficient of variation. Exploratory total volumes of distribution (V T ) were computed using an arterial input function and the Logan plot as well as a constrained 2-tissue-compartment model with the ratio of rate constants between plasma and tissue compartments ( K 1 / k 2 ) coupled (2TCM). SUV was correlated with V T to investigate its potential as a surrogate marker of GluN2B expression. Results: High and heterogeneous radioligand uptake was observed across the entire gray matter with reversible kinetics within the scan time. SUV absolute percentage difference ranged from 6.9% to 8.5% and coefficient of variation from 4.9% to 6.0%, indicating a high test-retest reliability. A moderate correlation was found between SUV averaged from 70 to 90 min and V T using Logan plot (Spearman ρ = 0.44). Correlation between V T Logan and 2TCM was r = 0.76. Conclusion: The radioligand ( R )- 11 C-Me-NB1 was highly effective in mapping GluN2B-enriched NMDARs in the human brain. With a heterogeneous uptake and a high test-retest reliability, this radioligand offers promise to deepen our understanding of the GluN2B-containing NMDAR in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer disease and major depression. Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: GluN2B containing N-methyl-D-aspartate receptors (NMDARs) play an essential role in neurotransmission and are a potential treatment target for multiple neurological and neurodegenerative diseases, including stroke, Alzheimer's disease, and Parkinson's disease. (R)-[ 18 F]OF-Me-NB1 was reported to be more specific and selective than (S)-[ 18 F]OF-Me-NB1 for the GluN2B subunits of the NMDAR based on their binding affinity to GluN2B and sigma-1 receptors. Here we report a comprehensive evaluation of (R)-[ 18 F]OF-Me-NB1 and (S)-[ 18 F]OF-Me-NB1 in nonhuman primates., Methods: The radiosynthesis of (R)-[ 18 F]OF-Me-NB1 and (S)-[ 18 F]OF-Me-NB1 started from 18 F-fluorination of the boronic ester precursor, followed by removal of the acetyl protecting group. PET scans in two rhesus monkeys were conducted on the Focus 220 scanner. Blocking studies were performed after treatment of the animals with the GluN2B antagonist Co101,244 or the sigma-1 receptor antagonist FTC-146. One-tissue compartment (1TC) model and multilinear analysis-1 (MA1) method with arterial input function were used to obtain the regional volume of distribution (V T , mL/cm 3 ). Occupancy values by the two blockers were obtained by the Lassen plot. Regional non-displaceable binding potential (BP ND ) was calculated from the corresponding baseline V T and the V ND derived from the occupancy plot of the Co101,244 blocking scans., Results: (R)- and (S)-[ 18 F]OF-Me-NB1 were produced in > 99% radiochemical and enantiomeric purity, with molar activity of 224.22 ± 161.69 MBq/nmol at the end of synthesis (n = 10). Metabolism was moderate, with ~ 30% parent compound remaining for (R)-[ 18 F]OF-Me-NB1 and 20% for (S)-[ 18 F]OF-Me-NB1 at 30 min postinjection. Plasma free fraction was 1-2%. In brain regions, both (R)- and (S)-[ 18 F]OF-Me-NB1 displayed fast uptake with slower clearance for the (R)- than (S)-enantiomer. For (R)-[ 18 F]OF-Me-NB1, both the 1TC model and MA1 method gave reliable estimates of regional V T values, with MA1 V T (mL/cm 3 ) values ranging from 8.9 in the cerebellum to 12.8 in the cingulate cortex. Blocking with 0.25 mg/kg of Co101,244 greatly reduced the uptake of (R)-[ 18 F]OF-Me-NB1 across all brain regions, resulting in occupancy of 77% and V ND of 6.36, while 0.027 mg/kg of FTC-146 reduced specific binding by 30%. Regional BP ND , as a measure of specific binding signals, ranged from 0.40 in the cerebellum to 1.01 in the cingulate cortex., Conclusions: In rhesus monkeys, (R)-[ 18 F]OF-Me-NB1 exhibited fast kinetics and heterogeneous uptake across brain regions, while the (S)-enantiomer displayed a narrower dynamic range of uptake across regions. A Blocking study with a GluN2B antagonist indicated binding specificity. The value of BP ND was > 0.5 in most brain regions, suggesting good in vivo specific binding signals. Taken together, results from the current study demonstrated the potential of (R)-[ 18 F]OF-Me-NB1 as a useful radiotracer for imaging the GluN2B receptors., (© 2022. The Author(s).)

The aim of this study was to identify a folate receptor-α (FRα)-selective PET agent potentially suitable for the selection of patients who might profit from FRα-targeted therapies. The 6 R and 6 S isomers of 18 F-aza-5-methyltetrahydrofolate (MTHF) were assessed regarding their binding to FRα and FRβ, expressed on cancer and inflammatory cells, respectively, and compared with 18 F-AzaFol, the folic acid-based analog. Methods: FR selectivity was investigated using FRα-transfected (RT16) and FRβ-transfected (D4) CHO cells. The cell uptake of 18 F-folate tracers was investigated, and receptor-binding affinities were determined with the nonradioactive analogs. In vitro autoradiography of the 18 F-folate tracers was performed using RT16 and D4 tissue sections. Biodistribution studies and PET/CT imaging of the radiotracers were performed on mice bearing RT16 and D4 xenografts. Results: The uptake of 18 F-6 R -aza-5-MTHF was high when using RT16 cells (62% ± 10% of added activity) but much lower when using D4 cells (5% ± 2%). The FRα selectivity of 18 F-6 R -aza-5-MTHF was further demonstrated by its approximately 43-fold higher binding affinity to FRα (half-maximal inhibitory concentration [IC 50 ], 1.8 ± 0.1 nM) than to FRβ (IC 50 , 77 ± 27 nM). The uptake of 18 F-6 S -aza-5-MTHF and 18 F-AzaFol was equal in both cell lines (52%-70%), with similar affinities to FRα (IC 50 , 2.1 ± 0.4 nM and 0.6 ± 0.3 nM, respectively) and FRβ (0.8 ± 0.2 nM and 0.3 ± 0.1 nM, respectively). The autoradiography signal obtained with 18 F-6 R -aza-5-MTHF was 11-fold more intense for RT16 than for D4 tissue sections. Biodistribution data showed high uptake of 18 F-6 R -aza-5-MTHF in RT16 xenografts (81% ± 20% injected activity per gram [IA]/g 1 h after injection) but significantly lower accumulation in D4 xenografts (7.3% ± 2.1% IA/g 1 h after injection), which was also visualized using PET. The uptake of 18 F-6 S -aza-5-MTHF and 18 F-AzaFol was similar in RT16 (53% ± 10% IA/g and 45% ± 2% IA/g, respectively) and D4 xenografts (77% ± 10% IA/g and 52% ± 7% IA/g, respectively). Conclusion: This study demonstrated FRα selectivity for 18 F-6 R -aza-5-MTHF but not for 18 F-6 S -aza-5-MTHF or 18 F-AzaFol. This characteristic, together with its favorable tissue distribution, makes 18 F-6 R -aza-5-MTHF attractive for clinical translation to enable detection of FRα-positive cancer while preventing undesired accumulation in FRβ-expressing inflammatory cells., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

A straightforward synthesis of a fluorine-18-labeled prodrug of AFA233 is reported. The key step in the preparation of [ 18 F]AFA233-prodrug is the selective deprotection of the tert -butyl protection groups of the quinoxalinedione moiety without cleavage of the tert -butyl- S -acyl-2-thioethyl protection groups on the phosphate esters. In addition, the preparation of the nonradioactive prodrug reference compound of AFA233 is reported.

Mavoglurant binds to same allosteric site on metabotropic glutamate receptor 5 (mGluR5) as [ 11 C]-ABP688, a radioligand. This open-label, single-center pilot study estimates extent of occupancy of mGluR5 receptors following single oral doses of mavoglurant, using [ 11 C]-ABP688 positron emission tomography (PET) imaging, in six healthy males aged 20-40 years. This study comprised three periods and six subjects were divided into two cohorts. On Day 1 (Period 1), baseline clinical data and safety samples were obtained along with PET scan. During Period 2 (1-7 days after Period 1), cohort 1 and 2 received mavoglurant 25 mg and 100 mg, respectively. During Period 3 (7 days after Period 2), cohort 1 and 2 received mavoglurant 200 mg and 400 mg, respectively. Mavoglurant showed the highest distribution volumes in the cingulate region with lower uptake in cerebellum and white matter, possibly because myelinated axonal sheets maybe devoid of mGlu5 receptors. Maximum concentrations of mavoglurant were observed around 2-3.25 h post-dose. Mavoglurant passed the blood-brain barrier and induced dose- and exposure-dependent displacement of [ 11 C]-ABP688 from the mGluR5 receptors, 3-4 h post-administration (27%, 59%, 74%, 85% receptor occupancy for mavoglurant 25 mg, 100 mg, 200 mg, 400 mg dose, respectively). There were no severe adverse effects or clinically significant changes in safety parameters. This is the first human receptor occupancy study completed with Mavoglurant. It served to guide the dosing of mavoglurant in the past and currently ongoing clinical studies. Furthermore, it confirms the utility of [ 11 C]-ABP688 as a unique tool to study drug-induced occupancy of mGlu5 receptors in the living human brain., Competing Interests: Declaration of Competing Interest JS, VT, AB, SA, MB, RPM have no conflict of interest; MES holds Novartis shares; AG, YPA, I-TV, BG-M, FG are employees of Novartis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

As part of our continuous efforts to develop a suitable 18 F-labeled PET radioligand with improved characteristics for imaging the N -methyl-d-aspartate receptors (NMDARs) subtype 2B (GluN1/2B), we investigated in the current work ortho -fluorinated (OF) and meta -fluorinated (MF) analogs of 18 F- para -fluorinated (PF)-NB1, a 3-benzazepine-based radiofluorinated probe. Methods: OF-NB1 and MF-NB1 were prepared using a multistep synthesis, and their binding affinities toward GluN2B subunits and selectivity over σ1 receptors (σ1Rs) were determined via competitive binding assays. 18 F-OF-NB1 was synthesized via copper-mediated radiofluorination and was evaluated in Wistar rats by in vitro autoradiography, PET imaging, ex vivo biodistribution, metabolite experiments, and receptor occupancy studies using CP-101,606, an established GluN2B antagonist. To determine in vivo selectivity, 18 F-OF-NB1 was validated in wild-type and σ1R knock-out mice. Translational relevance was assessed in autoradiographic studies using postmortem human brain tissues from healthy individuals and ALS patients, the results of which were corroborated by immunohistochemistry. Results: The binding affinity values for OF-NB1 and MF-NB1 toward the GluN2B subunits were 10.4 ± 4.7 and 590 ± 36 nM, respectively. For σ1R binding, OF-NB1 and MF-NB1 exhibited inhibition constants of 410 and 2,700 nM, respectively. OF-NB1, which outperformed MF-NB1, was radiolabeled with 18 F to afford 18 F-OF-NB1 in more than 95% radiochemical purity and molar activities of 192 ± 33 GBq/μmol. In autoradiography experiments, 18 F-OF-NB1 displayed a heterogeneous and specific binding in GluN2B subunit-rich brain regions such as the cortex, striatum, hypothalamus, and hippocampus. PET imaging studies in Wistar rats showed a similar heterogeneous uptake, and no brain radiometabolites were detected. A dose-dependent blocking effect was observed with CP-101,606 (0.5-15 mg/kg) and resulted in a 50% receptor occupancy of 8.1 μmol/kg. Postmortem autoradiography results revealed lower expression of the GluN2B subunits in ALS brain tissue sections than in healthy controls, in line with immunohistochemistry results. Conclusion: 18 F-OF-NB1 is a highly promising PET probe for imaging the GluN2B subunits of the N- methyl-d-aspartate receptor. It possesses utility for receptor occupancy studies and has potential for PET imaging studies in ALS patients and possibly other brain disorders., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Radiopharmacy at ETH has worked on the development of novel PET tracers for neuro-, cardiac- and tumor imaging for many years. In this paper, our efforts on targeting the glutamatergic system of the metabotropic glutamate receptor subtype 5 (mGluR5) and the ionotropic N -methyl-D-aspartate (NMDA) receptor are summarized. We briefly described the principles of positron emission tomography (PET) tracer development for the central nervous system (CNS) and the radiolabeling methods used in our laboratory. To assess the radioligands, results of in vitro autoradiography, biodistribution, and metabolite studies as well as PET imaging data are discussed. Furthermore, key PET parameters for kinetic modeling and quantification methods are provided. Two mGluR5 PET tracers, [ 11 C]ABP688 and [ 18 F]PSS232, were translated in our GMP labs and evaluated in human subjects. The newly developed GluN2B PET tracer [ 11 C]Me-NB1 is currently being investigated in a first-in-human PET study and several F-18 labeled tracers are being evaluated in non-human primates in which the first-in-class will be translated for human studies.

We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on a 5H-thiazolo[3,2-α]pyrimidin-5-one scaffold. The metabolic stability and overall properties could be optimized satisfactorily, although binding affinities remained a limiting factor for in vivo imaging. We nevertheless identified 7-(((2-fluoroethyl)(3-fluorophenyl)amino)-methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo-[3,2-α]pyrimidin-5-one ([ 18 F]7b) as a radioligand providing good-quality images in autoradiographic studies, as well as a tritiated derivative, 2-(7-(((2-fluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-α]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([ 3 H 2 ]15b), which was used for the successful development of a radioligand binding assay. These are valuable new tools for the study of GluN2A-containing NMDA receptors, and for the optimization of allosteric modulators binding to the pharmacophore located at the dimer interface of the GluN1-GluN2A ligand-binding domain., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic ( N -methyl- D -aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

Introduction: - The NMDA receptor is implicated in various diseases including neurodegenerative, neurodevelopmental and mood disorders. However, only a limited number of clinically approved NMDA receptor modulators are available. Today, apparent NMDA receptor drug development strategies entail 1) exploring the unknown chemical space to identify novel scaffolds; 2) using the clinically available NMDA receptor modulators to expand the therapeutic indication space; 3) and to trace physiological functions of the NMDA receptor., Areas Covered: - The current review reflects on the functional and pharmacological facets of NMDA receptors and the current clinical status quo of NMDA receptor modulators. Patent literature covering 2015 till April 2020 is discussed with emphasis on new indications., Expert Opinion: - Supporting evidence shows that subtype-selective NMDA receptor antagonists show an improved safety profile compared to broad-spectrum channel blockers. Although GluN2B-selective antagonists are by far the most extensively investigated subtype-selective modulators, they have shown only modest clinical efficacy so far. To overcome the limitations that have hampered the clinical development of previous subtype-selective NMDA receptor antagonists, future studies with improved animal models that better reflect human NMDA receptor pathophysiology are warranted. The increased availability of subtype-selective probes will allow target engagement studies and proper dose finding in future clinical trials.

Purpose: Clinical positron emission tomography (PET) imaging of the presynaptic norepinephrine transporter (NET) function provides valuable diagnostic information on sympathetic outflow and neuronal status. As data on the NET-targeting PET tracers [ 11 C]meta-hydroxyephedrine ([ 11 C]mHED) and [ 18 F]LMI1195 ([ 18 F]flubrobenguane) in murine experimental models are scarce or lacking, we performed a detailed characterization of their myocardial uptake pattern and investigated [ 11 C]mHED uptake by kinetic modelling., Methods: [ 11 C]mHED and [ 18 F]LMI1195 accumulation in the heart was studied by PET/CT in FVB/N mice. To test for specific uptake by NET, desipramine, a selective NET inhibitor, was administered by intraperitoneal injection. [ 11 C]mHED kinetic modelling with input function from an arteriovenous shunt was performed in three mice., Results: Both tracers accumulated in the mouse myocardium; however, only [ 11 C]mHED uptake was significantly reduced by excess amount of desipramine. Myocardial [ 11 C]mHED uptake was half-saturated at 88.3 nmol/kg of combined mHED and metaraminol residual. After [ 11 C]mHED injection, a radiometabolite was detected in plasma and urine, but not in the myocardium. [ 11 C]mHED kinetics followed serial two-tissue compartment models with desipramine-sensitive K 1 ., Conclusion: PET with [ 11 C]mHED but not [ 18 F]LMI1195 provides information on NET function in the mouse heart. [ 11 C]mHED PET is dose-independent in the mouse myocardium at < 10 nmol/kg of combined mHED and metaraminol. [ 11 C]mHED kinetics followed serial two-tissue compartment models with K 1 representing NET transport. Myocardial [ 11 C]mHED uptake obtained from PET images may be used to assess cardiac sympathetic integrity in mouse models of cardiovascular disease.

Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity ( K i for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18- d 6 exhibited outstanding in vitro performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% ( n = 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [ 18 F]RoSMA-18- d 6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [ 18 F]RoSMA-18- d 6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [ 18 F]RoSMA-18- d 6 is a promising CB2 PET radioligand for clinical translation.

Chronic stress leads to changes in energy status and is a major risk factor for depression, with common symptoms of reductions in body weight and effortful motivation for reward. Indeed, stress-induced disturbed energy status could be a major aetio-pathogenic factor for depression. Improved understanding of these putative inter-relationships requires animal model studies of effects of stress on both peripheral and central energy-status measures and determinants. Here we conducted a study in mice fed on a standard low-fat diet and exposed to either 15-day chronic social stress (CSS) or control handling (CON). Relative to CON mice, CSS mice had attenuated body weight maintenance/gain despite consuming the same amount of food and expending the same amount of energy at any given body weight. The low weight of CSS mice was associated with less white and brown adipose tissues, and with a high respiratory exchange ratio consistent with increased dependence on glucose as energy substrate. Basal plasma insulin was low in CSS mice and exogenous glucose challenge resulted in a relatively prolonged elevation of blood glucose. With regard to hunger and satiety hormones, respectively, CSS mice had higher levels of acylated ghrelin in plasma and of ghrelin receptor gene expression in ventromedial hypothalamus and lower levels of plasma leptin, relative to CON mice. However, whilst CSS mice displayed this constellation of peripheral changes consistent with increases in energy need and glucose utilization relative to CON mice, they also displayed attenuated uptake of [ 18 F]FDG in brain tissue specifically. Reduced brain glucose utilization in CSS mice could contribute to the reduced effortful motivation for reward in the form of sweet-tasting food that we have reported previously for CSS mice. It will now be important to utilize this model to further understanding of the mechanisms via which chronic stress can increase energy need but decrease brain glucose utilization and how this relates to regional and cellular changes in neural circuits for reward processing relevant to depression., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

[ 18 F]Flurpiridaz is a recently developed positron emission tomography tracer that is currently being investigated in phase III clinical trials to measure myocardial blood flow. The relatively long physical half-life of fluorine-18 alongside the high spatial resolution and outstanding myocardium-to-background ratio fuels its potential to be the next gold standard for the early detection of coronary artery disease. Notwithstanding the expected widespread use of [ 18 F]flurpiridaz, the reported multistep synthesis of its precursor for radiofluorination involves a hazardous alkylation step using carcinogenic ethylene oxide, and a low overall chemical yield of 7 %. In this work, we have improved the overall yield more than fivefold and concurrently replaced the hazardous step. Specificity of binding of [ 18 F]flurpiridaz to mitochondrial complex 1 was demonstrated by in vitro autoradiography on mouse heart tissue sections. These results thus pave the way for assessing myocardial blood flow and coronary flow reserve in mouse models of cardiovascular disease., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The folate receptor-α (FR-α) is overexpressed in many epithelial cancers, including ovary, uterus, kidneys, breast, lung, colon and prostate carcinomas, but shows limited expression in normal tissues such as kidneys, salivary glands, choroid plexus and placenta. FR-α has therefore emerged as a promising target for the delivery of therapeutic and imaging agents to FR-positive tumors. A series of folate-based PET (positron emission tomography) radiopharmaceuticals have been developed for the selective targeting of FR-positive malignancies. This review provides an overview on the research progress made so far regarding the design, radiosynthesis and the utility of the folate-derived PET radioconjugates for targeting FR-positive tumors. For the most part, results from folate radioconjugates labeled with fluorine-18 (t 1/2 = 109.8 min) and gallium-68 (t 1/2 = 67.7 min) have been presented but folates labeled with "exotic" and new PET radionuclides such as copper-64 (t 1/2 = 12.7 h), terbium-152 (t 1/2 = 17.5 h), scandium-44 (t 1/2 = 3.97 h), cobalt-55 (t 1/2 = 17.5 h) and zirconium-89 (t 1/2 = 78.4 h) are also discussed. For tumor imaging, none of the reported PET radiolabeled folates reported to date has made the complete bench-to-bedside journey except [ 18 F]AzaFol, which made it to patients with metastatic ovarian and lung cancers in a multicenter first-in-human trial. In the near future, however, we expect more clinical trials with folate-based PET radiopharmaceuticals given the increasing clinical interest in imaging and the treatment of FR-related malignancies.

Introduction: Metabotropic glutamate receptors play a critical role in the pathogenesis of Alzheimer's disease due to their involvement in processes of memory formation, neuroplasticity, and synaptotoxity. The objective of the current study was to study mGluR5 availability measured by [ 11 C]-ABP688 (ABP) in patients with clinically diagnosed Alzheimer's dementia (AD)., Methods: A bolus-infusion protocol of [ 11 C]-ABP688 was applied in 9 subjects with AD and 10 cognitively healthy controls (Controls) to derive distribution volume estimates of mGluR5. Furthermore, we also estimated cerebral perfusion by averaging early frame signal of initial ABP bolus injection., Results: Subjects with Alzheimer's dementia (mean age: 77.3/SD 5.7) were older than controls (mean age: 68.5/SD: 9.6) and scored lower on the MMSE (22.1/SD2.7 vs. 29.0/SD0.8). There were no overall differences in ABP signal. However, distribution volume ratio (DVR) for ABP was reduced in the bilateral hippocampus (AD: 1.34/SD: 0.40 vs. Control: 1.84/SD:0.31, p = .007) and the bilateral amygdala (AD:1.86/SD:0.26 vs. Control:2.33/SD:0.37 p = .006) in AD patients compared to controls. Estimate of cerebral blood flow was reduced in the bilateral hippocampus in AD (AD:0.75/SD:0.10 vs. Control:0.86/SD:0.09 p = .02)., Conclusion: Our findings demonstrate reduced mGluR5 binding in the hippocampus and amygdala in Alzheimer's dementia. Whether this is due to synaptic loss and/or consecutive reduction of potential binding sites or reflects disease inherent mechanisms remains to be elucidated in future studies., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Bulimia nervosa (BN) shares central features with substance-related and addictive disorders. The metabotropic glutamate receptor subtype 5 (mGlu5) plays an important role in addiction. Based on similarities between binge eating and substance-related and addictive disorders, we investigated mGlu5 in vivo in 15 female subjects with BN and 15 matched controls. We measured mGlu5 distribution volume ratio (DVR) with positron emission tomography (PET) using [11 C]ABP688. In BN mGlu5 DVR was higher in the anterior cingulate cortex (ACC), subgenual prefrontal cortex, and straight gyrus (p < 0.05). In BN, higher mGlu5 DVR in various brain regions, including ACC, pallidum, putamen, and caudate, positively correlated with "maturity fears" as assessed using the Eating Disorder Inventory-2 (p < 0.05). In BN and controls, smokers had globally decreased mGlu5 DVR. We present the first evidence for increased mGlu5 DVR in BN. Our findings suggest that pharmacological agents inhibiting mGlu5 might have a therapeutic potential in BN.

Background: The folate receptor alpha (FRα) is an interesting target for imaging and therapy of different cancers. We present the first in-human radiation dosimetry and radiation safety results acquired within a prospective, multicentric trial (NCT03242993) evaluating the 18 F-AzaFol (3'-aza-2'-[ 18 F]fluorofolic acid) as the first clinically assessed PET tracer targeting the FRα., Material and Methods: Six eligible patients presented a histologically confirmed adenocarcinoma of the lung with measurable lesions (≥ 10 mm according to RECIST 1.1). TOF-PET images were acquired at 3, 11, 18, 30, 40, 50, and 60 min after the intravenous injection of 327 MBq (range 299-399 MBq) of 18 F-AzaFol to establish dosimetry. Organ absorbed doses (AD), tumor AD, and patient effective doses (E) were assessed using the OLINDA/EXM v.2.0 software and compared with pre-clinical results., Results: No serious related adverse events were observed. The highest AD were in the liver, the kidneys, the urinary bladder, and the spleen (51.9, 45.8, 39.1, and 35.4 μGy/MBq, respectively). Estimated patient and gender-averaged E were 18.0 ± 2.6 and 19.7 ± 1.4 μSv/MBq, respectively. E in-human exceeded the value of 14.0 μSv/MBq extrapolated from pre-clinical data. Average tumor AD was 34.8 μGy/MBq (range 13.6-60.5 μGy/MBq)., Conclusions: 18 F-Azafol is a PET agent with favorable dosimetric properties and a reasonable radiation dose burden for patients which merits further evaluation to assess its performance., Trial Registration: ClinicalTrial.gov, NCT03242993, posted on August 8, 2017.

A new prosthetic group is reported for 18F-labelling of peptides and proteins based on the chemoselective ligation of potassium acyltrifluoroborates (KATs) and hydroxylamines without any detectable 18F/19F isotope exchange at the acyltrifluoroborate moiety. The new building block is appended via a common amide bond at room temperature with no need for protecting groups which enables an effective orthogonal 18F-radiolabelling.

The cannabinoid type 2 (CB2) receptor has emerged as a valuable target for therapy and imaging of immune-mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 positron emission tomography (PET) radioligand [ 11 C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a K i (hCB2) of 6 nM and a selectivity factor of nearly 700 over cannabinoid type 1 receptors, target compound 3 exhibited optimal in vitro properties and was selected for evaluation as a PET radioligand. [ 18 F] 3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [ 18 F] 3 to CB2 was demonstrated by in vitro autoradiography and in vivo PET experiments using the CB2 ligand GW-405 833. Metabolite analysis revealed only intact [ 18 F] 3 in the rat brain. [ 18 F] 3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.

Aspiring to develop a positron emission tomography (PET) imaging agent for the GluN2B subunits of the N -methyl-d-aspartate receptor (NMDAR), a key therapeutic target for drug development toward several neurological disorders, we synthesized a series of 2,3,4,5-tetrahydro-1 H -3-benzazepine and 6,7,8,9-tetrahydro-5 H -benzo[7]annulen-7-amine analogues. After in vitro testing via competition binding assay and autoradiography, [ 18 F]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over σ1 and σ2 receptors and was thus selected for further in vivo evaluation. Copper-mediated radiofluorination was accomplished in good radiochemical yields and high molar activities. Extensive in vivo characterization was performed in Wistar rats comprising PET imaging, biodistribution, receptor occupancy, and metabolites studies. [ 18 F]PF-NB1 binding was selective to GluN2B-rich forebrain regions and was specifically blocked by the GluN2B antagonist, CP-101,606, in a dose-dependent manner with no brain radiometabolites. [ 18 F]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.

Using positron emission tomography (PET), a profound alteration of the metabotropic glutamate receptor 5 (mGluR5) was found in human smoking addiction and abstinence. As human PET data either reflect the impact of chronic nicotine exposure or a pre-existing vulnerability to nicotine addiction, we designed a preclinical, longitudinal study to investigate the effect of chronic nicotine exposure on mGluR5 with the novel radiotracer [ 18 F]PSS232 using PET. Twelve male dark Agouti rats at the age of 6 weeks were assigned randomly to three groups. From day 0 to day 250 the groups received 0 mg/L, 4 mg/L, or 8 mg/L nicotine solution in the drinking water. From day 250 to 320 all groups received nicotine-free drinking water. PET scans with [ 18 F]PSS232 were performed in all animals on days 0, 250, and 320. To assess locomotion, seven tests in square open field arenas were carried out 72 days after the last PET scan. During the first four tests, rats received 0 mg/L nicotine and for the last three tests 4 mg/L nicotine in the drinking water. After 250 days of nicotine consumption [ 18 F]PSS232 binding was reduced in the striatum, hippocampus, thalamus, and midbrain. At day 320, after nicotine withdrawal, [ 18 F]PSS232 binding increased. These effects were more pronounced in the 4 mg/L nicotine group. Chronic administration of nicotine through the drinking water reduced exploratory behaviour. This preliminary longitudinal PET study demonstrates that chronic nicotine administration alters behaviour and mGluR5 availability. Chronic nicotine administration leads to decreased [ 18 F]PSS232 binding which normalizes after prolonged nicotine withdrawal.

Sleep and brain glutamatergic signaling are homeostatically regulated. Recovery sleep following prolonged wakefulness restores efficient functioning of the brain, possibly by keeping glutamatergic signaling in a homeostatic range. Evidence in humans and mice suggested that metabotropic glutamate receptors of subtype-5 (mGluR5) contribute to the brain's coping mechanisms with sleep deprivation. Here, proton magnetic resonance spectroscopy in 31 healthy men was used to quantify the levels of glutamate (Glu), glutamate-to-glutamine ratio (GLX), and γ-amino-butyric-acid (GABA) in basal ganglia (BG) and dorsolateral prefrontal cortex on 3 consecutive days, after ~8 (baseline), ~32 (sleep deprivation), and ~8 hours (recovery sleep) of wakefulness. Simultaneously, mGluR5 availability was quantified with the novel radioligand for positron emission tomography, [18F]PSS232, and the blood levels of the mGluR5-regulated proteins, fragile X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF) were determined. The data revealed that GLX (p = 0.03) in BG (for Glu: p < 0.06) and the serum concentration of FMRP (p < 0.04) were increased after sleep loss. Other brain metabolites (GABA, N-acetyl-aspartate, choline, glutathione) and serum BDNF levels were not altered by sleep deprivation (pall > 0.6). By contrast, the night without sleep enhanced whole-brain, BG, and parietal cortex mGluR5 availability, which was normalized by recovery sleep (pall < 0.05). The findings provide convergent multimodal evidence that glutamatergic signaling is affected by sleep deprivation and recovery sleep. They support a role for mGluR5 and FMRP in sleep-wake regulation and warrant further studies to investigate their causality and relevance for regulating human sleep in health and disease. Clinical Trial Registration: www.clinicaltrials.gov (study identifier: NCT03813082)., (© Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].)

The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure-affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 ( 7f ) was radiolabeled with carbon-11. In vitro, [ 11 C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [ 11 C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.

The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in β- or γ-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in γ-position possess higher GluN2B affinity than analogs bearing the F-atom in β-position. This effect was attributed to the reduced basicity of β-fluoro amines. 3-Benzazepines with a benzylic OH moiety show moderate GluN2B affinity, but considerable selectivity over the σ 2 receptor. However, removal of the benzylic OH moiety led to increased GluN2B affinity, but reduced GluN2B/σ 2 selectivity. With respect to GluN2B affinity the phenol 17b with a γ-fluorophenylbutyl moiety in 3-position represents the most interesting fluorinated ligand (K i (GluN2B) = 16 nM). Most of the synthesized ligands reveal either similar GluN2B and σ 1 affinity or higher σ 1 affinity than GluN2B affinity. The methyl ether 16b shows high σ 1 affinity (K i (σ 1 ) = 6.6 nM) and high selectivity over a broad panel of receptors and transporters. The high antiallodynic activity in the mouse capsaicin assay proved the σ 1 antagonistic activity of 16b., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Excitotoxicity driven by overactivation of NMDA receptors represents a major mechanism of acute and chronic neurological and neurodegenerative disorders. Negative allosteric modulators interacting with the ifenprodil binding site of the NMDA receptor are able to interrupt this ongoing neurodamaging process. Starting from the potent 3-benzazepine-1,7-diol 4a novel NMDA receptor antagonists were designed by modification of the N-(4-phenylbutyl) side chain. With respect to developing novel fluorinated PET tracers, regioisomeric fluoroethoxy derivatives 11, 12, 14, and 15 were synthesized. Analogs 19 and 20 with various heteroaryl moieties at the end of the N-side chain were prepared by Sonogashira reaction and nucleophilic substitution. The fluoroethyl triazole 37 was obtained by 1,3-dipolar cycloaddition. In several new ligands, the flexibility of the (hetero)arylbutyl side chain was restricted by incorporation of a triple bond. The affinity towards the ifenprodil binding site was tested in an established competition assay using [ 3 H]ifenprodil as radioligand. Introduction of a fluoroethoxy moiety at the terminal phenyl ring, replacement of the terminal phenyl ring by a heteroaryl ring and incorporation of a triple bond into the butyl spacer led to considerable reduction of GluN2B affinity. The phenol 15 (K i  = 193 nM) bearing a p-fluoroethoxy moiety at the terminal phenyl ring represents the most promising GluN2B ligand of this series of compounds. With exception of 15 showing moderate σ 2 affinity (K i  = 79 nM), the interaction of synthesized 3-benzazepines towards the PCP binding site of the NMDA receptor, σ 1 and σ 2 receptors was rather low (K i  > 100 nM)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Recently, the eutomers of highly potent GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold were identified. Herein, pharmacokinetic properties regarding lipophilicity, plasma protein binding (PPB) and metabolism are analyzed. The logD 7.4 values of 1.68 for phenol 1 and 2.46 for methyl ether 2 are in a very good range for CNS agents. A very similar logD 7.4 value was recorded for the prototypical GluN2B antagonist ifenprodil (logD 7.4  = 1.49). The herein developed high performance affinity chromatography (HPAC) method using human serum albumin as stationary phase led to PPB of 3-benzazepines (R)-1-3 and (S)-1-3 of 76-98%. Upon incubation with mouse liver microsomes, (R)-1-3 and (S)-1-3 showed moderate to high metabolic stability. The (R)-configured eutomers turned out to be metabolically more stable than their (S)-configured distomers. During phase I metabolism of 3-benzazepines 1-3 hydroxylations at both aromatic rings, the aliphatic side chain and the seven-membered ring were observed. O-demethylation of methyl ether (S)-2 was faster than O-demethylation of its enantiomer (R)-2. In phase I biotransformation the phenol eutomer (R)-1 showed comparable stability as ifenprodil. In phase II biotransformation, glucuronidation of the phenolic (only 1) and benzylic hydroxy groups was observed. Both enantiomers formed the same type of metabolites, respectively, but in different amounts. Whereas, the benzylic hydroxy group of (R)-2 was glucuronidated preferably, predominant benzylic glucuronidation of (S)-3 was detected. Mouse liver microsomes produced the glucuronide of phenol 1 (main metabolite) in larger amounts than rat liver microsomes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The study aims to investigate the performance characteristics of the enantiomers of 11 C-Me-NB1, a recently reported PET imaging probe that targets the GluN2B subunit of N -methyl-d-aspartate (NMDA) receptors. Methods: Reference compound Me-NB1 (inhibition constant for hGluN1/GluN2B, 5.4 nM) and the phenolic precursor were prepared via multistep synthesis. Following chiral resolution by high-performance liquid chromatography, enantiopure precursor compounds, ( R ) - NB1 and ( S ) - NB1, were labeled with 11 C and validated in rodents using in vitro/ex vivo autoradiography, PET experiments, and dose-response studies. To illustrate the translational relevance, ( R ) - 11 C-Me-NB1 was validated in autoradiographic studies using postmortem human GluN2B-rich cortical and GluN2B-deficient cerebellar brain slices. To determine target engagement, receptor occupancy was assessed at different plasma concentrations of CP101,606, a GluN2B receptor antagonist. Results: The radiosynthesis of ( R ) - and ( S ) - 11 C-Me-NB1 was accomplished in 42% ± 9% (decay-corrected) radiochemical yields. Molar activity ranged from 40 to 336 GBq/μmol, and an excellent radiochemical purity of greater than 99% was achieved. Although ( R ) - 11 C-Me-NB1 displayed heterogeneous accumulation with high selectivity for the GluN2B-rich forebrain, ( S ) - 11 C-Me-NB1 revealed a homogeneous distribution across all brain regions in rodent brain autoradiograms and predominantly exhibited σ 1 -receptor binding. Similar to rodent brain, ( R ) - 11 C-Me-NB1 showed in postmortem human brain tissues higher binding in the cortex than in the cerebellum. Coincubation of the GluN2B-antagonist CERC-301 (1 μM) reduced cortical but not cerebellar binding, demonstrating the specificity of ( R ) - 11 C-Me-NB1 binding to the human GluN2B-containing NMDA receptor. In vivo specificity of ( R ) - 11 C-Me-NB1 in the GluN2B-expressing cortex, striatum, thalamus, and hippocampus was demonstrated by PET imaging in rodents. Applying GluN2B-antagonist eliprodil, an evident dose-response behavior was observed with ( R ) - 11 C-Me-NB1 but not with ( S ) - 11 C-Me-NB1. Our findings further underline the tightrope walk between GluN2B- and σ 1 -receptor-targeted imaging, illustrated by the entirely different receptor binding behavior of the 2 radioligand enantiomers. Conclusion: ( R ) - 11 C-Me-NB1 is a highly selective and specific PET radioligand for imaging the GluN2B subunit of the NMDA receptor. The entirely different receptor binding behavior of ( R ) - 11 C-Me-NB1 and ( S ) - 11 C-Me-NB1 raises awareness of a delicate balance that is underlying the selective targeting of either GluN2B-carrying NMDA or σ 1 -receptors., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

N-methyl-D-aspartate (NMDA) receptors play key roles in physiology by regulating the synaptic plasticity and the cellular mechanism involved in learning and memory. The GluN2A subunit is the most abundant expression of NMDA receptors in mature brain, and its dysfunction has been implicated in various neurological disorders. However, the function of GluN2A subunit in physiological and pathological conditions is not yet completely unveil due to the lack of subunit-selective ligands, including specific positron emission tomography (PET)/single photon emission computed tomography (SPECT) imaging probes. In this review, recent progresses in understanding its pathophysiological role, the structure-activity relationship, and the postulated mechanisms of novel GluN2A ligands as well as status of molecular imaging probes for PET are summarized., (© 2019 John Wiley & Sons, Ltd.)

Because of their neuroprotective potential, GluN2B-selective ligands are of great interest for the treatment of various neurological and neurodegenerative disorders. Fluorinated benzo[7]annulen-7-amines, capable for PET, were synthesized by combining fluorinated phenylalkylamines with differently substituted ketones. Relationships between substitution pattern and GluN2B affinity as well as selectivity towards σ 1 and σ 2 receptors were investigated. Two promising ligands (18a and 20c) were selected for further pharmacological evaluation. Besides a slight serotonin transporter (SERT), norepinephrine transporter (NET), and hERG affinity, they did not show interaction with other targets. Furthermore, the pK a value of a set fluorinated ligands, bearing the fluorine atom in different positions, was determined., (© 2019 John Wiley & Sons, Ltd.)

Purpose: (E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone O-(3-(2-[ 18 F]-fluoroethoxy)propyl) oxime ([ 18 F]-PSS232) is a new PET tracer for imaging of metabotropic glutamate receptor subtype 5 (mGlu5), and has shown promising results in rodents and humans. The aim of this study was to estimate the radiation dosimetry and biodistribution in humans, to assess dose-limiting organs, and to demonstrate safety and tolerability of [ 18 F]-PSS232 in healthy volunteers., Methods: PET/CT scans of six healthy male volunteers (mean age 23.5 ± 1.7; 21-26 years) were obtained after intravenous administration of 243 ± 3 MBq of [ 18 F]-PSS232. Serial whole-body (vertex to mid-thigh) PET scans were assessed at ten time points, up to 90 min after tracer injection. Calculation of tracer kinetics and cumulated organ activities were performed using PMOD 3.7 software. Dosimetry estimates were calculated using the OLINDA/EXM software., Results: Injection of [ 18 F]-PSS232 was safe and well tolerated. Organs with highest absorbed doses were the gallbladder wall (0.2295 mGy/MBq), liver (0.0547 mGy/MBq), and the small intestine (0.0643 mGy/MBq). Mean effective dose was 3.72 ± 0.12 mSv/volunteer (range 3.61-3.96 mSv; 0.0153 mSv/MBq)., Conclusion: [ 18 F]-PSS232, a novel [ 18 F]-labeled mGlu5 tracer, showed favorable dosimetry values. Additionally, the tracer was safe and well tolerated.

Purpose: The aim of the present study was to determine the expression levels of mGluR5 in different mouse strains after induction of neuroinflammation by lipopolysaccharide (LPS) challenge and in the brains of patients with Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) post mortem to investigate mGluR5 expression in human neurodegenerative diseases., Methods: C57BL/6 and CD1 mice were injected intraperitoneally with either 10 mg/kg LPS or saline. mGluR5 and TSPO mRNA levels were measured after 1 and 5 days by qPCR, and mGluR5 protein levels were determined by PET imaging with the mGluR5-specific radiotracer [ 18 F]PSS232. mGluR5 expression was evaluated in the post-mortem brain slices from AD and ALS patients using in vitro autoradiography., Results: mGluR5 and TSPO mRNA levels were increased in brains of C57BL/6 and CD1 mice 1 day after LPS treatment and remained significantly increased after 5 days in C57BL/6 mice but not in CD1 mice. Brain PET imaging with [ 18 F]PSS232 confirmed increased mGluR5 levels in the brains of both mouse strains 1 day after LPS treatment. After 5 days, mGluR5 levels in CD1 mice declined to the levels in vehicle-treated mice but remained high in C57BL/6 mice. Autoradiograms revealed a severalfold higher binding of [ 18 F]PSS232 in post-mortem brain slices from AD and ALS patients compared with the binding in control brains., Conclusion: LPS-induced neuroinflammation increased mGluR5 levels in mouse brain and is dependent on the mouse strain and time after LPS treatment. mGluR5 levels were also increased in human AD and ALS brains in vitro. PET imaging of mGluR5 levels could potentially be used to diagnose and monitor therapy outcomes in patients with AD and ALS.