This is the fourth in a series of studies that suggest that depressive behavior in adult female cynomolgus monkeys is similar to that observed in humans. It has been observed in 2 large groups of monkeys randomly selected from feral populations, suggesting that the capacity for depression is inherent in the species. This animal model holds promise to further our understanding of the basic mechanisms of affective behavior, the neuropathophysiologic characteristics of depression and the cognitive dysfunction that accompanies them, genetic and environmental factors that may affect depression risk, and the role of reproductive function in the excess depression risk in women.

The kappa opioid receptors (KOR) are involved in mood disorders and addictive conditions. In vivo imaging studies of this receptor in humans have not been reported due to the lack of a selective ligand. We employed a recently developed selective KOR agonist tracer, [11C]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 a total of 12 scans with [11C]GR103545 on the Focus 220 scanner under baseline and self-blocking conditions. The injected mass was 0.042±0.014 µg/kg for the baseline scans and ranged from 0.17 to 0.3 µg/kg for the self-blocking scans. The radiotracer was administered in a bolus plus infusion (B+I) protocol, and cerebellum used as 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 post tracer administration in a given region of interest (ROI) and in the cerebellum. In six scans, arterial input functions and free fraction in plasma (fp) were measured, and a 2 -tissue compartment model was used to compute the volume of distribution in the cerebellum (VT_REF), which was then employed to estimate the free to non-displaceable concentration ratio (fND) as fp/VT_REF. A Scatchard plot was used to estimate Bmax, and KdND = Kd/fND, the Kd value with respect to the cerebellar concentration. Individual data were first analyzed separately, then pooled together. When KdND was allowed to vary among ROIs, results were very variable; therefore KdND 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 KdND. Estimated Bmax ranged from 0.3 to 6.1 nM across ROIs and animals. The Kd estimate of 0.048 nM, obtained by correcting KdND by the factor fND, was between the in vitro Kd values of 0.018 nM to 0.4 nM (obtained from functional assays in rabbit vas deferens and radioligand competition assays using cloned human receptors, respectively). Based on these data, a suitable tracer dose of 0.02 µg/kg was selected for use in humans. Conclusions The use of a B+I protocol with the KOR agonist tracer [11C]GR103545 permitted the successful estimation of Bmax and KdND in vivo. Based on the estimated Kd value, a tracer dose of 1.4 µg (3.38 nmol) for an average body weight of 70 k g was chosen as the mass dose limit in human studies using this novel agonist radiotracer.

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The pancreas is one of the most heavily innervated peripheral organs in the body. Parasympathetic and sympathetic neurons terminate in the pancreas and provide tight control of endocrine and exocrine functions. The aim of this study was to determine whether the pancreas can be imaged with a radioligand that binds to specific neuroreceptors. Using fluorine-18 4-fluorobenzyltrozamicol (FBT), which binds to the presynaptic vesicular acetylcholine transporter, positron emission tomography scans were performed in four adult mice, two adult rhesus monkeys, and one adult human. In these mammals, the pancreas is intensely FBT avid, with uptake greater than in any other organ at 30, 60, and 90 min. The maximum standardized uptake value (SUV) ratios of pancreas to liver, for example, ranged from 1.4 to 1.7 in rhesus monkeys (mean 1.6; median 1.7) and from 1.9 to 4.7 (mean 3.24; median 3.02) in mice. The maximum SUV ratio of pancreas to liver in the human was 1.8. These data suggest that neuroreceptor imaging of the pancreas in vivo is feasible in animal models and humans. This imaging could allow researchers to interrogate functions under control of the autonomic nervous system in the pancreas, with applications possible in transplanted and native pancreata. Also, as beta cell function is intimately related to parasympathetic cholinergic input, FBT activity in the pancreas may correlate with insulin-producing beta cell mass. This could ultimately provide a method of in vivo imaging in animal models and humans for diabetes research.

Purpose: In colorectal, breast, and head and neck cancers, response to 5-fluorouracil is associated with low expression of thymidylate synthase. In contrast, tumors with high expression of thymidylate synthase may be more sensitive to prodrugs such as 1-(2-deoxy-2-fluoro-␤-D-arabinofuranosyl) uracil (FAU) that are activated by thymidylate synthase. These studies were designed to evaluate FAU as a potential therapeutic and diagnostic probe. Results: Thymidylate synthase enzymatic activity in LS174T xenografts was ϳ3.5-fold higher than in HT29 xenografts, and incorporation of radioactivity derived from