Development Of New Approaches To Neuroimaging with PET a

National Institute On Drug Abuse

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Abstract

PET Section The ability to image and quantify nicotinic receptors in human brain may be crucial to better understanding the neurobiology of smoking addiction. Analogs of A-85380 and A-84543 have been evaluated as imaging agents for nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) and single photon emission computed tomography (SPECT). Radiation dosimetry and toxicological studies in animals demonstrated the safety of 5-[I-125]iodo-A-85380 (5IA). In collaboration with Yale University, the SPECT studies with 5IA revealed that cerebral nAChRs can be quantified in human non-smoking volunteers. Similarly, the first human PET studies in non-smokers with 2-[F-18]fluoro-A-85380 (2FA) demonstrated the feasibility of quantitatively imaging nAChRs in the thalamus and visualizing these receptors in brain regions containing low to moderate receptor densities and that multiple studies on a single volunteer are possible within dosimetry limits. Additionally, the cardiovascular safety of 2FA in humans was established by demonstrating the lack of effects on blood pressure and electrocardiograms. Mice studies showed that the administration of the non-selective inhibitor of cytochrome P450, cimetidine, substantially slowed the rapid in vivo metabolism of 5IA, suggesting that the use of this or similar compounds could reduce the dose of radioactivity needed to successfully image nAChRs in human volunteers. Graphical analysis of PET data from Rhesus monkeys provided binding potential values for 2FA in the thalamus, cortex, striatum and cerebellum that were consistent with the distribution pattern of alpha4beta2* nAChRs. Methodology was developed and data were collected for estimating the density of nAChRs in the thalamus of non-human primates (NHPs). In collaboration with researchers from the University of Michigan, the loss of nAChRs in the striatum of unilaterally MPTP-lesioned NHPs with 2FA and PET was demonstrated. Kinetic studies with 2FA and PET in NHPs revealed that 2FA accumulates relatively slowly in brain, partially because its low lipophilicity slows its blood-brain-barrier penetration. A series of 5-heteryl-6-halogeno-A-85380 derivatives with binding affinity (Ki) at the nicotinic acetylcholine receptor (nAChR) ranging from 3 to 150 pM and a lipophilicity (logD) range of -1.6 to +1.5 has been synthesized as potential PET ligands. Most ligands of the series exhibited a higher binding affinity at the alpha4beta2* subtype of nAChRs than epibatidine. Molecular modeling studies revealed an important role of the orientation of the external heterocyclic ring on the binding affinity of the ligands with nAChRs. Two compounds of the series were radiolabeled with 18F. Recent PET studies with one of these compounds ([18F]NIDA52189) demonstrated that its binding potential values in Rhesus monkey brain was ca. 2.5 times that of 2-[18F]F-A-85380, the only available PET radiotracer for imaging cerebral nAChR in humans. Therefore we conclude that [18F]NIDA52189 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs. Exploration of the central CB1 cannabinoid receptors using PET will allow for an understanding of the pharmacological and physiological role played by these receptors in the CNS. Current tracers are highly lipophilic compounds that exhibit very high nonspecific to specific binding ratios and as a result are inapt for use in humans. We have synthesized a series of less lipophilic analogues of SR141716 to serve as potential radioligands. Some of these compounds possess lower lipophilicity values and comparable binding affinity to SR141716. A facile method for the synthesis of C-4 fluoro analogues of SR141716 has been developed and using a functional electrophysiological assay, we demonstrated that several compounds of the series possess antagonistic properties and are able to rapidly and completely reverse the effects of WIN55,221-2. The methoxy analogue of SR141716 was selected as a potential target for the development of corresponding 11C and H3-labeled derivatives. Greater accumulation of radioactivity after administration of this compound to mice was observed in CB1-rich regions (e.g., hippocampus, striatum and cerebellum) than in receptor poor brain regions, suggesting specific binding to these receptors. Similar findings were obtained in PET studies of Rhesus monkeys. CRH acts as a major regulator of the hypothalamic-pituitary-adrenal (HPA) axis coordinating neuroendocrine, autonomic, immune, and behavioral responses to stress. It is prevalent in the central nervous system (CNS) where it acts as a neurotransmitter. A high-affinity, nonpeptide radioligand for the CRHR1 was synthesized and showed distribution in rat brain consistent with CRHR1 using in vitro autoradiography. This is the first nonpeptide radiotracer combining high affinity and appropriate lipophilicity that penetrates the blood-brain barrier and hence has the potential to be used for PET imaging studies. In vivo visualization of changes in the CRH1 receptor or its occupancy would further the understanding of the role of stress in drug abuse.