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Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [(11)C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [(11)C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [(11)C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively--OMAR VT, anandamide and cortisol--correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder.

Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [11C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [11C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [11C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively-OMAR VT, anandamide and cortisol-correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder. [ABSTRACT FROM AUTHOR]

The neural bases of autism are poorly understood at the molecular level, but evidence from animal models, genetics, post-mortem studies, and single-gene disorders implicate synaptopathology. Here, we use positron emission tomography (PET) to assess the density of synapses with synaptic vesicle glycoprotein 2A (SV2A) in autistic adults using 11 C-UCB-J. Twelve autistic (mean (SD) age 25 (4) years; six males), and twenty demographically matched non-autistic individuals (26 (3) years; eleven males) participated in a 11 C-UCB-J PET scan. Binding potential, BP ND , was the primary outcome measure and computed with the centrum semiovale as the reference region. Partial volume correction with Iterative Yang was applied to control for possible volumetric differences. Mixed-model statistics were calculated for between-group differences. Relationships to clinical characteristics were evaluated based on clinician ratings of autistic features. Whole cortex synaptic density was 17% lower in the autism group (p = 0.01). All brain regions in autism had lower 11 C-UCB-J BP ND compared to non-autistic participants. This effect was evident in all brain regions implicated in autism. Significant differences were observed across multiple individual regions, including the prefrontal cortex (-15%, p = 0.02), with differences most pronounced in gray matter (p < 0.0001). Synaptic density was significantly associated with clinical measures across the whole cortex (r = 0.67, p = 0.02) and multiple regions (rs = -0.58 to -0.82, ps = 0.05 to <0.01). The first in vivo investigation of synaptic density in autism with PET reveals pervasive and large-scale lower density in the cortex and across multiple brain areas. Synaptic density also correlated with clinical features, such that a greater number of autistic features were associated with lower synaptic density. These results indicate that brain-wide synaptic density may represent an as-yet-undiscovered molecular basis for the clinical phenotype of autism and associated pervasive alterations across a diversity of neural processes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The sphingosine-1-phosphate receptor-1 (S1PR 1 ) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR 1 -specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR 1 radiotracer, [ 18 F]TZ4877, in nonhuman primates., Procedures: [ 18 F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[ 18 F]/F - followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120-180 min following bolus injection of 118-163 MBq [ 18 F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction ( f P ). Each animal was scanned at baseline, 15-18 min after 0.047-0.063 mg/kg of the S1PR 1 inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR 1 -specific compound TZ82112, and 167-195 min after 1 ng/kg of the immune stimulus endotoxin. Kinetic analysis with metabolite-corrected input function was performed to estimate the free fraction corrected total distribution volume ( V T / f P ). Whole-body dosimetry scans were acquired in 2 animals (1M, 1F) with a Biograph Vision PET/CT System, and absorbed radiation dose estimates were calculated with OLINDA., Results: [ 18 F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [ 18 F]TZ4877 f P was low (< 1%), and [ 18 F]TZ4877 V T / f P values were 233-866 mL/cm 3 . TZ82112 dose-dependently reduced [ 18 F]TZ4877 V T / f P , while ponesimod and endotoxin exhibited negligible effects on V T / f P , possibly due to scan timing relative to dosing. Dosimetry studies identified the critical organs of gallbladder (0.42 (M) and 0.31 (F) mSv/MBq) for anesthetized nonhuman primate., Conclusions: [ 18 F]TZ4877 exhibits reversible kinetic properties, but the low f P value limits quantification with this radiotracer. S1PR 1 is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Parkinson's disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [ 11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [ 11 C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [ 11 C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions., (© 2024. The Author(s).)

PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, ( R )-4-(3-( 18 F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one ( 18 F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with 18 F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume ( V T ). The regional nondisplaceable binding potential ( BP ND ) was calculated from 1TC V T , using the centrum semiovale (CS) as the reference region. Results: 18 F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of 18 F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). 18 F-SynVesT-2 entered the brain quickly, with an SUV peak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, V T was estimated more reliably using the 1TC model. The 1TC V T ranged from 1.9 ± 0.2 mL/cm 3 C-UCB-J and 3 in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BP ND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable V T and BP ND Conclusion: 18 F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of 18 F-SynVesT-2 is faster than the kinetics of 11 C-UCB-J and 18 F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The sigma-2 receptor (σ2R), recently identified as transmembrane protein 97, is expressed in many cell types and mediates important functions in both the peripheral and central nervous systems. Over the years, σ2R has emerged as a potential therapeutic target for cancer and neurological disorders such as Alzheimer's disease (AD). The currently available σ2R radiotracers have been developed primarily for cancer imaging with limited brain uptake. Here, we report the evaluation of the first brain penetrant 18 F-labeled radiotracer suitable for positron emission tomography (PET) imaging of σ2R in nonhuman primate brain.

Purpose: Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl- 11 C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([ 11 C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates., Methods: We synthesized [ 11 C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [ 11 C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (V T ), nondisplaceable volume of distribution (V ND ), and nondisplaceable binding potential (BP ND ) in selected brain regions., Results: [ 11 C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [ 11 C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [ 11 C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BP ND  > 3) and low nonspecific uptake (V ND  < 3 mL/cm 3 ) in the monkey brain., Conclusion: [ 11 C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [ 11 C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [ 11 C]PyBic to have broad applications in oncology and neuroimaging., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [ 11 C]OCM-44 and [ 18 F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03-0.25 mg/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [ 11 C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [ 11 C]OCM-44 volume of distribution ( V T ) values in the brain increased with time; V T values from models fitted to truncated 60-min scan data were 1.4-2.9 mL/cm 3 across brain regions. The plasma free fraction was 0.6% for [ 18 F]OCM-50 and V T values (120-min) were 0.39-0.87 mL/cm 3 in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional V T indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [ 11 C]OCM-44 and [ 18 F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis.

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.)

Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [ 11 C]raclopride positron emission tomography three times-at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [ 11 C]raclopride binding potential (ΔBP ND ) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Tobacco smoking is a major public health burden. The first-line pharmacological treatment for tobacco smoking is nicotine replacement therapy (eg, the nicotine patch (NIC)). Nicotine acts on nicotinic-acetylcholine receptors on dopamine terminals to release dopamine in the ventral and dorsal striatum encoding reward and habit formation, respectively., Aims and Methods: To better understand treatment efficacy, a naturalistic experimental design combined with a kinetic model designed to characterize smoking-induced dopamine release in vivo was used. Thirty-five tobacco smokers (16 female) wore a NIC (21 mg, daily) for 1-week and a placebo patch (PBO) for 1-week in a randomized, counter-balanced order. Following 1-week under NIC and then overnight abstinence, smokers participated in a 90-minute [11C]raclopride positron emission tomography scan and smoked a cigarette while in the scanner. Identical procedures were followed for the PBO scan. A time-varying kinetic model was used at the voxel level to model transient dopamine release peaking instantaneously at the start of the stimulus and decaying exponentially. Magnitude and spatial extent of dopamine release were estimated. Smokers were subcategorized by nicotine dependence level and nicotine metabolism rate., Results: Dopamine release magnitude was enhanced by NIC in ventral striatum and diminished by NIC in dorsal striatum. More-dependent smokers activated more voxels than the less-dependent smokers under both conditions. Under PBO, fast metabolizers activated more voxels in ventral striatum and fewer voxels in dorsal striatum compared to slow metabolizers., Conclusions: These findings demonstrate that the model captured a pattern of transient dopamine responses to cigarette smoking which may be different across smoker subgroup categorizations., Implications: This is the first study to show that NIC alters highly localized patterns of cigarette smoking-induced dopamine release and that levels of nicotine dependence and nicotine clearance rate contribute to these alterations. This current work included a homogeneous subject sample with regards to demographic and smoking variables, as well as a highly sensitive model capable of detecting significant acute dopamine transients. The findings of this study add support to the recent identification of biomarkers for predicting the effect of nicotine replacement therapies on dopamine function which could help refine clinical practice for smoking cessation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Purpose: Exploring synaptic density changes during brain growth is crucial to understanding brain development. Previous studies in nonhuman primates report a rapid increase in synapse number between the late gestational period and the early neonatal period, such that synaptic density approaches adult levels by birth. Prenatal synaptic development may have an enduring impact on postnatal brain development, but precisely how synaptic density changes in utero are unknown because current methods to quantify synaptic density are invasive and require post-mortem brain tissue., Methods: We used synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) radioligands [ 11 C]UCB-J and [ 18 F]Syn-VesT-1 to conduct the first assessment of synaptic density in the developing fetal brain in gravid rhesus monkeys. Eight pregnant monkeys were scanned twice during the third trimester at two imaging sites. Fetal post-mortem samples were collected near term in a subset of subjects to quantify SV2A density by Western blot., Results: Image-derived fetal brain SV2A measures increased during the third trimester. SV2A concentrations were greater in subcortical regions than in cortical regions at both gestational ages. Near term, SV2A density was higher in primary motor and visual areas than respective associative regions. Post-mortem quantification of SV2A density was significantly correlated with regional SV2A PET measures., Conclusion: While further study is needed to determine the exact relationship of SV2A and synaptic density, the imaging paradigm developed in the current study allows for the effective in vivo study of SV2A development in the fetal brain., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The descending raphespinal serotonin (5-HT) system contributes to neural activities required for locomotion. The presynaptic serotonin transporter (SERT) is a marker of 5-HT innervation. In this study, we explored the use of PET imaging with the SERT radioligand [ 11 C]AFM as a biomarker of 5-HT axon damage after spinal cord injury (SCI) in a rodent model and its translation to imaging SCI in humans., Procedures: PET imaging with [ 11 C]AFM was performed in healthy rats under baseline and citalopram blocking conditions and a mid-thoracic transection rat model of SCI. The lumbar-to-cervical activity (L/C) ratio was calculated for the healthy and SCI animals to assess SERT binding decrease after SCI. Finally, translation of [ 11 C]AFM PET was attempted to explore its potential to image SCI in humans., Results: Intense uptake in the brain and intact spinal cord was observed at 30-60 min post-injection of [ 11 C]AFM in healthy rats. About 65% of [ 11 C]AFM uptake in the spinal cord was blocked by citalopram. In the SCI rat model, the cervical uptake of [ 11 C]AFM was similar to that in healthy rats, but the lumbar uptake was dramatically reduced, resulting in about half the L/C ratio in SCI rats compared to healthy rats. In contrast, [ 11 C]AFM uptake in the human spinal cord showed no obvious decrease after treatment with citalopram. In the human subjects with SCI, decreases in [ 11 C]AFM uptake were also not obvious in the section of spinal cord caudal to the injury point., Conclusion: [ 11 C]AFM PET imaging of SERT provides a useful preclinical method to non-invasively visualize the rodent spinal cord and detect SERT changes in SCI rodent models. However, there appears to be little detectable specific binding signal for [ 11 C]AFM in the human spinal cord. An SERT tracer with higher affinity and lower non-specific binding signal is needed to image the spinal cord in humans and to assess the axonal status in SCI patients., (© 2022. World Molecular Imaging Society.)

Purpose: Neuronal damage and synapse loss in the spinal cord (SC) have been implicated in spinal cord injury (SCI) and neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS). Current standards of diagnosis for SCI include CT or MRI imaging to evaluate injury severity. The current study explores the use of PET imaging with [ 11 C]UCB-J, which targets the synaptic vesicle protein 2A (SV2A), in the human spinal cord, as a way to visualize synaptic density and integrity in vivo., Results: First, simulations of baseline and blocking [ 11 C]UCB-J HRRT scans were performed, based on SC dimensions and SV2A distribution to predict V T , V ND , and V S values. Next, human baseline and blocking [ 11 C]UCB-J HRRT images were used to estimate these values in the cervical SC (cSC). Simulation results had excellent agreement with observed values of V T , V ND , and V S from the real human data, with baseline V T , V ND , and V S of 3.07, 2.15, and 0.92 mL/cm 3 , respectively, with a BP ND of 0.43. Lastly, we explored full SC imaging with whole-body images. Using automated SC regions of interest (ROIs) for the full SC, cSC, and thoracic SC (tSC), the distribution volume ratio (DVR) was estimated using the brain gray matter as a reference region to evaluate SC SV2A density relative to the brain. In full body imaging, DVR values of full SC, cSC, and tSC were 0.115, 0.145, and 0.112, respectively. Therefore, measured [ 11 C]UCB-J uptake, and thus SV2A density, is much lower in the SC than in the brain., Conclusions: The results presented here provide evidence for the feasibility of SV2A PET imaging in the human SC, however, specific binding of [ 11 C]UCB-J is low. Ongoing and future work include further classification of SV2A distribution in the SC as well as exploring higher-affinity PET radioligands for SC imaging., (© 2022. The Author(s).)

Arginine vasopressin is a hormone that is synthesized mainly in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least 3 subtypes (V 1A , V 1B , and V 2 ). Among these subtypes, the V 1B receptor (V 1B R), highly expressed in the pituitary, is a primary regulator of hypothalamic-pituitary-adrenal axis activity and thus a potential target for treatment of neuropsychiatric disorders such as depression and anxiety. N - tert -butyl-2-[2-(6-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4 H )-yl]acetamide (TASP699) is a novel PET radiotracer with high affinity and selectivity for V 1B R. The purpose of this study was to characterize the pharmacokinetic and binding profiles of 11 C-TASP699 in humans and determine its utility in an occupancy study of a novel V 1B R antagonist, TS-121. Methods: Six healthy subjects were scanned twice with 11 C-TASP699 to determine the most appropriate kinetic model for analysis of imaging data and test-retest reproducibility of outcome measures. Nine healthy subjects were scanned before and after administration of TS-121 (active component: THY1773) to assess V 1B R occupancy. Metabolite-corrected arterial input functions were obtained. Pituitary time-activity curves were analyzed with 1- and 2-tissue-compartment (1TC and 2TC, respectively) models and multilinear analysis 1 (MA1) to calculate distribution volume ( V T ). Relative test-retest variability (TRV) and absolute TRV were calculated. Since no brain region could be used as a reference region, percentage change in V T after TS-121 administration was computed to assess its receptor occupancy and correlate with plasma concentrations of the drug. Results: 11 C-TASP699 showed high uptake in the pituitary and no uptake in any brain region. The 2TC model provided better fits than the 1TC model. Because the MA1 V T estimates were similar to the 2TC V T estimates, MA1 was the model of choice. The TRV of V T was good (TRV, -2% ± 14%; absolute TRV, 11%). THY1773 reduced V T in a dose-dependent fashion, with a half-maximal inhibitory concentration of 177 ± 52 ng/mL in plasma concentration. There were no adverse events resulting in discontinuation from the study. Conclusion: 11 C-TASP699 was shown to display appropriate kinetics in humans, with substantial specific binding and good reproducibility of V T Therefore, this tracer is suitable for measurement of V 1B R in the human pituitary and the V 1B R occupancy of TS-121, a novel V 1B R antagonist., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and [ 11 C]UCB-J-a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine's therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine's therapeutic effects., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Sites of early neuropathologic change provide important clues regarding the initial clinical features of Alzheimer's disease (AD). We have shown significant reductions in hippocampal synaptic density in participants with AD, consistent with the early degeneration of entorhinal cortical (ERC) cells that project to hippocampus via the perforant path. In this study, [ 11 C]UCB-J binding to synaptic vesicle glycoprotein 2A (SV2A) and [ 18 F]flortaucipir binding to tau were measured via PET in 10 participants with AD (5 mild cognitive impairment, 5 mild dementia) and 10 cognitively normal participants. In the overall sample, ERC tau was inversely associated with hippocampal synaptic density (r = -0.59, p = 0.009). After correction for partial volume effects, the association of ERC tau with hippocampal synaptic density was stronger in the overall sample (r = -0.61, p = 0.007) and in the AD group where the effect size was large, but not statistically significant (r = -0.58, p = 0.06). This inverse association of ERC tau and hippocampal synaptic density may reflect synaptic failure due to tau pathology in ERC neurons projecting to the hippocampus., (Copyright © 2021. Published by Elsevier Inc.)

Background: Synaptic injury is a pathological hallmark of neurological impairment in people living with human immunodeficiency virus (HIV, PLWH), a common complication despite viral suppression with antiretroviral therapy (ART). Measurement of synaptic density in living humans may allow better understanding of HIV neuropathogenesis and provide a dynamic biomarker for therapeutic studies. We applied novel synaptic vesical protein 2A (SV2A) positron emission tomographic (PET) imaging to investigate synaptic density in the frontostriatalthalamic region in PLWH and HIV-uninfected participants., Methods: In this cross-sectional pilot study,13 older male PLWH on ART underwent magnetic resonance imaging (MRI) and PET scanning with the SV2A ligand [11C]UCB-J with partial volume correction and had neurocognitive assessments. SV2A binding potential (BPND) in the frontostriatalthalamic circuit was compared to 13 age-matched HIV-uninfected participants and assessed with respect to neurocognitive performance in PLWH., Results: PLWH had 14% lower frontostriatalthalamic SV2A synaptic density compared to HIV-uninfected (PLWH: mean [SD], 3.93 [0.80]; HIV-uninfected: 4.59 [0.43]; P = .02, effect size 1.02). Differences were observed in widespread additional regions in exploratory analyses. Higher frontostriatalthalamic SV2A BPND associated with better grooved pegboard performance, a measure of motor coordination, in PLWH (r = 0.61, P = .03)., Conclusions: In a pilot study, SV2A PET imaging reveals reduced synaptic density in older male PLWH on ART compared to HIV-uninfected in the frontostriatalthalamic circuit and other cortical areas. Larger studies controlling for factors in addition to age are needed to determine whether differences are attributable to HIV or comorbidities in PLWH. SV2A imaging is a promising biomarker for studies of neuropathogenesis and therapeutic interventions in HIV., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: Metabotropic glutamate receptor subtype 5 (mGluR5) is integral to the brain glutamatergic system and cognitive function. This study investigated whether aging is associated with decreased brain mGluR5 availability., Methods: Cognitively normal participants (n = 45), aged 18 to 84 years, underwent [ 18 F]FPEB positron emission tomography scans to quantify brain mGluR5. Distribution volume (V T ) was computed using a venous or arterial input function and equilibrium modeling from 90 to 120 min. In the primary analysis, the association between age and V T in the hippocampus and association cortex was evaluated using a linear mixed model. Exploratory analyses assessed the association between age and V T in multiple brain regions. The contribution of gray matter tissue alterations and partial volume effects to associations with age was also examined., Results: In the primary analysis, older age was associated with lower [ 18 F]FPEB binding to mGluR5 (P = 0.026), whereas this association was not significant after gray matter masking or partial volume correction to account for age-related tissue loss. Post hoc analyses revealed an age-related decline in mGluR5 availability in the hippocampus of 4.5% per decade (P = 0.007) and a non-significant trend in the association cortex (P = 0.085). An exploratory analysis of multiple brain regions revealed broader inverse associations of age with mGluR5 availability, but not after partial volume correction., Conclusion: Reductions in mGluR5 availability with age appear to be largely mediated by tissue loss. Quantification of [ 18 F]FPEB binding to mGluR5 may expand our understanding of age-related molecular changes and the relationship with brain tissue loss., Competing Interests: Declaration of Competing Interest The authors have no actual or potential conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Cannabis is one of the most commonly and widely used psychoactive drugs. The rates of cannabis misuse have been increasing. Therefore, understanding the effects of cannabis use on the brain is important. Adolescent and adult rodents exposed to repeated administration of cannabinoids show persistent microstructural changes in the hippocampus both pre- and post-synaptically. Whether similar alterations exist in human cannabis users, has not yet been demonstrated in vivo. Positron emission tomography (PET) and [ 11 C]UCB-J, a radioligand for the synaptic vesicle glycoprotein 2A (SV2A), were used to study hippocampal synaptic integrity in vivo in an equal number (n = 12) of subjects with DSM-5 cannabis use disorder (CUD) and matched healthy controls (HC). Arterial sampling was used to measure plasma input function. [11C]UCB-J binding potential (BP ND ) was estimated using a one-tissue (1T) compartment model with centrum semiovale as the reference region. Hippocampal function was assessed using a verbal memory task. Relative to HCs, CUDs showed significantly lower [ 11 C]UCB-J BP ND in the hippocampus (~10%, p = 0.008, effect size 1.2) and also performed worse on the verbal memory task. These group differences in hippocampal BP ND persisted after correction for volume differences (p = 0.013), and correction for both age and volume (p = 0.03). We demonstrate, for the first time, in vivo evidence of lower hippocampal synaptic density in cannabis use disorder. These results are consistent with the microstructural findings from experimental studies with cannabinoids in animals, and studies of hippocampal macrostructure in human with CUD. Whether the lower hippocampal synaptic density resolves with abstinence warrants further study., (© 2020. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Acetylcholine (ACh) has distinct functional roles in striatum compared with cortex, and imbalance between these systems may contribute to neuropsychiatric disease. Preclinical studies indicate markedly higher ACh concentrations in the striatum. The goal of this work was to leverage positron emission tomography (PET) imaging estimates of drug occupancy at cholinergic receptors to explore ACh variation across the human brain, because these measures can be influenced by competition with endogenous neurotransmitter. PET scans were analyzed from healthy human volunteers (n = 4) and nonhuman primates (n = 2) scanned with the M1-selective radiotracer [11C]LSN3172176 in the presence of muscarinic antagonist scopolamine, and human volunteers (n = 10) scanned with the α4β2* nicotinic ligand (-)-[18F]flubatine during nicotine challenge. In all cases, occupancy estimates within striatal regions were consistently lower (M1/scopolamine human scans, 31 ± 3.4% occupancy in striatum, 43 ± 2.9% in extrastriatal regions, p = 0.0094; nonhuman primate scans, 42 ± 26% vs. 69 ± 28%, p < 0.0001; α4β2*/nicotine scans, 67 ± 15% vs. 74 ± 16%, p = 0.0065), indicating higher striatal ACh concentration. Subject-level measures of these concentration differences were estimated, and whole-brain images of regional ACh concentration gradients were generated. These results constitute the first in vivo estimates of regional variation in ACh concentration in the living brain and offer a novel experimental method to assess potential ACh imbalances in clinical populations., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [ 18 F]SynVesT-1 and demonstrated its excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with [ 11 C]UCB-J., Methods: Three rhesus monkeys underwent whole body dynamic PET scanning to estimate the absorbed dose. PET scans in six healthy human subjects were acquired. Time-activity curves (TACs) were generated with defined regions of interest (ROI). Reproducibility of distribution volume (V T ) values and its sensitivity to scan duration were assessed with the one-tissue compartment (1TC) model. Non-displaceable binding potential (BP ND ) was calculated using centrum semiovale as the reference region., Results: The dosimetry study showed high uptake in the urinary bladder and brain. In humans, [ 18 F]SynVesT-1 displayed high uptake with maximum SUV of ~10 and appropriate kinetics with a quick rise in tracer uptake followed by a gradual clearance. Mean 1TC V T values (mL/cm 3 ) ranged from 3.4 (centrum semiovale) to 19.6 (putamen) and were similar to those of [ 11 C]UCB-J. Regional BP ND values were 2.7-4.7 in gray matter areas, and mean BP ND values across all ROIs were ~ 21% higher than those of [ 11 C]UCB-J. The absolute test-retest variability of V T and BP ND was excellent (< 9%) across all brain regions., Conclusions: [ 18 F]SynVesT-1 demonstrates outstanding characteristics in humans: fast and high brain uptake, appropriate tissue kinetics, high levels of specific binding, and excellent test-retest reproducibility of binding parameters. As such, [ 18 F]SynVesT-1 is proved to be a favorable radiotracer for SV2A imaging and quantification in humans.

The positron emission tomography radioligand [ 11 C]UCB-J binds to synaptic vesicle glycoprotein 2 A (SV2A), a regulator of vesicle release. Increased neuronal firing could potentially affect tracer concentrations if binding site availability is altered during vesicle exocytosis. This study assessed whether physiological brain activation induces changes in [ 11 C]UCB-J tissue influx ( K 1 ), volume of distribution ( V T ), or binding potential ( BP C]UCB-J PET scans at baseline and during intermittent presentation of 8-Hz checkerboard visual stimulation. Sensitivity to intermittent changes in kinetic parameters was assessed in simulations, and visual stimulation was repeated using functional magnetic resonance imaging to characterize neural responses. ND ). Healthy volunteers ( n  = 7) underwent 60-min [ 11 C]UCB-J PET scans at baseline and during intermittent presentation of 8-Hz checkerboard visual stimulation. Sensitivity to intermittent changes in kinetic parameters was assessed in simulations, and visual stimulation was repeated using functional magnetic resonance imaging to characterize neural responses. V T  and K 1 were determined using the one-tissue compartment model and BP ND using the simplified reference tissue model. In primary visual cortex, K 1 increased 34.3 ± 15.5% ( p  = 0.001) during stimulation, with no change in other regions ( p s   >   0.12). K 1 change was correlated with fMRI BOLD response (r = 0.77, p  = 0.043). There was no change in V T C]UCB-J p  =   0.33) or BP ND (-0.2 ± 9.6%, p  =   0.94) in visual cortex nor other regions ( p s   >   0.19). Therefore, despite robust increases in regional tracer influx due to blood flow increases, binding measures were unchanged during stimulation. [ 11 C]UCB-J V T and BP ND are likely to be stable in vivo measures of synaptic density.