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Introduction: Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [(11)C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (V(ND)) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated., Methods: For determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [(11)C]GR103545. Seven subjects were scanned before and 75 min after oral administration of naltrexone (150 mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5 h and 8 h after an oral dose of PF-04455242 (15 mg, n=1 and 30 mg, n=5). Metabolite-corrected arterial input functions were measured and all scans were 150 min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (V(T)). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and V(ND). The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [(11)C]GR103545 in vivo K(D) was also estimated., Results: Regional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that V(T) was reduced in all regions; thus no suitable reference region is available for the radiotracer. V(ND) was estimated reliably from the occupancy plot of naltrexone blocking (V(ND)=3.4±0.9 mL/cm(3)). The IC50 of PF-04455242 was calculated as 55 ng/mL. [(11)C]GR103545 in vivo K(D) value was estimated as 0.069 nmol/L., Conclusions: [(11)C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: The κ-opioid receptors (KOR) are involved in mood disorders and addictive conditions. In vivo imaging studies of this receptor in humans have not been reported because of the lack of a selective ligand. We used a recently developed selective KOR agonist tracer, (11)C-GR103545, and performed a study in rhesus monkeys to estimate the in vivo receptor concentration (Bmax) and dissociation equilibrium constant (Kd)., Methods: Four rhesus monkeys underwent 12 scans with (11)C-GR103545 on a PET scanner under baseline and self-blocking conditions. The injected mass was 0.042 ± 0.014 μg/kg for the baseline scans and ranged from 0.16 to 0.3 μg/kg for the self-blocking scans. The radiotracer was administered in a bolus-plus-infusion protocol, and cerebellum was used as the reference region in kinetic analysis. Binding potential (BPND) values were computed as [(CROI/CREF) - 1], where CROI and CREF are the mean of the radioactivity concentrations from 90 to 120 min after tracer administration in a given region of interest (ROI) and in the cerebellum. In 6 scans, arterial input functions and free fraction in plasma (fp) were measured. In addition, a 2-tissue-compartment model was used to compute the volume of distribution in the cerebellum (VT_REF), which was then used to estimate the free-to-nondisplaceable concentration ratio (fND) as fp/VT_REF. A Scatchard plot was used to estimate Bmax, and Kd(ND) = Kd/fND, the Kd value with respect to the cerebellar concentration. Individual data were first analyzed separately and then pooled together. When Kd(ND) was allowed to vary among ROIs, results were variable; therefore, Kd(ND) was constrained to be constant across ROIs, whereas Bmax was allowed to be ROI-dependent and animal-dependent., Results: A global estimate of 1.72 nM was obtained for Kd(ND). Estimated Bmax ranged from 0.3 to 6.1 nM across ROIs and animals. The Kd estimate of 0.048 nM, obtained by correcting Kd(ND) by the factor fND, was in good agreement with the half maximal inhibitory concentration (IC50) of 0.018 nM determined from functional assays in rabbit vas deferens and inhibition constant (Ki) of 0.02 nM measured in radioligand competition assays using cloned human receptors. On the basis of these data, a suitable tracer dose of 0.02 μg/kg was selected for use in humans., Conclusion: The use of a bolus-plus-infusion protocol with the KOR agonist tracer (11)C-GR103545 permitted the successful estimation of Bmax and Kd(ND) in vivo. On the basis of the estimated Kd value, a tracer dose of 1.4 μg (3.38 nmol) for an average body weight of 70 kg was chosen as the mass dose limit in human studies using this novel agonist radiotracer.

The main objective of the current study was to determine the sensitivity of the positron emission tomography (PET) radioligand [¹¹C]P943 to fenfluramine-induced changes in endogenous 5-HT in nonhuman primate brain. Fenfluramine-induced changes in 5-HT(1B) occupancy were compared to those obtained by self-block with unlabeled P943. Two baboons and 1 rhesus monkey were given preblocking or displacing doses of fenfluramine (1-5 mg/kg) or preblocking doses of unlabeled P943 (0.2 mg/kg) and imaged with [¹¹C]P943 PET. Receptor occupancy by the low dose of fenfluramine (1 mg/kg) in the baboons was 25 and 29% and by the high dose of fenfluramine (5 mg/kg) in the rhesus macaque was 42%. Receptor occupancy by P943 (0.2 mg/kg) was 68 and 86% in the baboons. PET imaging of 5-HT(1B) receptors with [¹¹C]P943 may be a useful approach for measuring changes in endogenous 5-HT in the living human brain., (Copyright © 2011 Wiley-Liss, Inc.)

The serotonin 5-HT(1B) receptors regulate the release of serotonin and are involved in various disease states, including depression and schizophrenia. The goal of the study was to evaluate a high affinity and high selectivity antagonist, [(11)C]P943, as a positron emission tomography (PET) tracer for imaging the 5-HT(1B) receptor. [(11)C]P943 was synthesized via N-methylation of the precursor with [(11)C]methyl iodide or [(11)C]methyl triflate using automated modules. The average radiochemical yield was approx. 10% with radiochemical purity of >99% and specific activity of 8.8+/-3.6 mCi/nmol at the end-of-synthesis (n=37). PET imaging was performed in non-human primates with a high-resolution research tomograph scanner with a bolus/infusion paradigm. Binding potential (BP(ND)) was calculated using the equilibrium ratios of regions to cerebellum. The tracer uptake was highest in the globus pallidus and occipital cortex, moderate in basal ganglia and thalamus, and lowest in the cerebellum, which is consistent with the known brain distribution of 5-HT(1B) receptors. Infusion of tracer at different specific activities (by adding various amount of unlabeled P943) reduced BP(ND) values in a dose-dependent manner, demonstrating the saturability of the tracer binding. Blocking studies with GR127935 (2 mg/kg iv), a selective 5-HT(1B)/5-HT(1D) antagonist, resulted in reduction of BP(ND) values by 42-95% across regions; for an example, in occipital region from 0.71 to 0.03, indicating a complete blockade. These results demonstrate the saturability and specificity of [(11)C]P943 for 5-HT(1B) receptors, suggesting its suitability as a PET radiotracer for in vivo evaluations of the 5-HT(1B) receptor system in humans., ((c) 2010 Elsevier Inc. All rights reserved.)