Endocannabinoids and their attending cannabinoid type 1 receptor (CB1) have been implicated in animal models of posttraumatic 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 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 (MR) imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [11C]OMAR, which measures volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), 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=.001; 19.5% and 14.5% higher, respectively) which were most pronounced in women (F(1,53)=5.52, p=.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.

The use of synaptic vesicle protein 2A (SV2A) radiotracers with positron emission tomography (PET) imaging could provide a way to measure synaptic density quantitatively in living humans. 11 C-UCB-J, previously developed and assessed in nonhuman primates and humans, showed excellent kinetic properties as a PET radioligand. However, it is labeled with the short half-life isotope 11 C. We developed a new tracer, an 18 F-labeled difluoro-analog of UCB-J ( 18 F-SynVesT-1, a.k.a. 18 F-SDM-8), which displayed favorable properties in monkeys. The purpose of this first-inhuman study was to assess the kinetic and binding properties of 18 F-SynVesT-1 and compare with 11 C-UCB-J.Methods: Eight healthy volunteers participated in a baseline study of 18 F-SynVesT-1. Four of these subjects were also scanned after a blocking dose of the anti-epileptic drug levetiracetam (20 mg/kg).Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were analyzed using one-and two-tissue compartment (1TC, 2TC) models and multilinear analysis 1 (MA1) to compute distribution volume (V T ) and binding potential (BP ND ). The centrum semiovale was used as a reference region. The Lassen plot was applied to compute levetiracetam occupancy and non-displaceable distribution volume (V ND ). Standardized uptake value ratio (SUVR) -1 over several time windows was compared with BP ND . Results: Regional TACs were fitted better with the 2TC model than the 1TC model, but 2TC V T estimates were unstable. The 1TC V T values matched well with those from the 2TC model (excluding the unstable values), Thus, 1TC was judged as the most useful model for quantitative analysis of 18 F-SynVesT-1 imaging data. Minimum scan time for stable V T measurement was 60 min. The rank order of V T and BP ND values was similar between 18 F-SynVesT-1 and 11 C-UCB-J.Regional V T values were slightly higher for 11 C-UCB-J, but BP ND values were higher for 18 F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of 18 F-SynVesT-1 in all regions and produced occupancy of 85.7%. SUVR-1 of 18 F-SynVesT-1 from 60-90 min matched best with 1TC BP ND . Conclusion:The novel SV2A tracer, 18 F-SynVesT-1, displays excellent kinetic and in vivo binding properties in humans and holds great potential for the imaging and quantification of synaptic density in neuropsychiatric disorders.

Kappa opioid receptors (KOR) are believed to be involved in the pathophysiology of depression, anxiety disorders, drug abuse and alcoholism. To date, only one tracer, the kappa opioid receptor agonist [11C]GR103545, has been reported to be able to image KOR in primates. The goal of the present study was to synthesize the selective KOR antagonist [11C]LY2795050 and evaluate its potential as a PET tracer to image KOR in vivo. METHODS In vitro binding affinity of LY2795050 was measured in radioligand competition binding assays. Ex vivo experiments were conducted using microdosing of the unlabelled ligand in Sprague-Dawley rats, as well as wild-type and KOR knock-out mice, to assess the ligand’s potential as a tracer candidate. Imaging experiments with [11C]LY2795050 in monkeys were carried out on the Focus-220 PET scanner with arterial blood input function measurement. Binding parameters were determined with kinetic modeling analysis. RESULTS LY2795050 displays full antagonist activity and high binding affinity and selectivity for KOR. Microdosing studies in rodents and ex vivo analysis of tissue concentrations with LC/MS/MS identified LY2795050 as an appropriate tracer candidate able to provide specific binding signals in vivo. [11C]LY2795050 was prepared in an average yield of 12% and >99% radiochemical purity. In rhesus monkeys, [11C]LY2795050 displayed a moderate rate of peripheral metabolism, with ∼40% of parent compound remaining at 30 min postinjection. In the brain, [11C]LY2795050 displayed fast uptake kinetics (regional activity peak times < 20 min) and an uptake pattern consistent with the distribution of KOR in primates. Pretreatment with naloxone (1 mg/kg, iv) resulted in a uniform distribution of radioactivity. Further, specific binding of [11C]LY2795050 was reduced by the selective KOR antagonist LY2456302 in a dose-dependent manner. CONCLUSION [11C]LY2795050 displayed favorable pharmacokinetic properties and binding profiles in vivo, and therefore is a suitable ligand for imaging the KOR in primates. This newly developed KOR antagonist tracer has since been advanced to PET imaging of KOR in humans and constitutes the first successful KOR antagonist radiotracer.