In this application new radioligands which bind to the serotonin (5-HT) reuptake site will be evaluated for use with single photon emission computed tomography (SPECT) and positron emission tomography (PET). The ultimate goal of the project is the use of these ligands to study neurochemical mechanisms in Alzheimer's disease (AD) and parkinson's disease (PD). The tracers will provide a measure of presynaptic degeneration in these diseases which may explain the basis for a variety of symptoms including psychosis and depression, and help define the biologic basis of disease heterogeneity, develop rational pharmacologic treatment, and elucidate the role of serotonin in normal human behavior. Promising preliminary data for one compound, 5-iodo-6-nitroquipazine (NQP), are presented. Experiments using [125I]-labelled NQP in rats shows high affinity binding and pharmacologic specificity. SPECT imaging of [123I]- NQP in monkeys shows in vivo visualization of serotonergic terminals in the cortex and brainstem, and pharmacologic behavior in blocking conditions indicate binding to the 5-HT reuptake site. The major portion of the grant will be devoted to validation of SPECT studies in nonhuman primates. A series of experiments will use macaca mulatta to study the kinetics of specific and nonspecific binding in the brain, as well as the time course of plasma radioactivity and metabolites. Once the optimal time point for imaging specific binding is known, blocking experiments, using drugs with known pharmacologic activity at a variety of different receptors will be performed to demonstrate pharmacologic specificity. Comparisons of tracer distribution to regional cerebral blood flow will also be performed. Finally, an experiment using animals lesioned with serotonergic neurotoxin MDMA will demonstrate the sensitivity of the technique for the detection of loss of presynaptic terminals, which will be validated by comparing tahe SPECT images to those obtained with in vivo autoradiography using the coinjected [125]-labelled tracer in the same animals. The focus of these experiments is to characterize the behavior of the tracer in primate brain with the key goal of validating the use of ratios of region-to-cerebellar activity as an index of specific binding. In addition, two other tracers will be investigated as possible ligands for PET studies of the reuptake site; [18F]-5-fluoro-6-nitroquipazine, and an [18F]-labelled analogue of McN-5652Z. Similar validation experiments using these PET ligands will be performed in monkeys. Once these experiments are concluded, human studies will begin with the investigation of the kinetics of one of these tracers in young control subjects. These experiments, in conjunction with data collected in the nonhuman primate studies, will help select the time point with the maximal specific/nonspecific binding. Subsequently, a small group of AD and PD patients and age matched controls will be studied in order to generate data for a larger scale clinical study using serotonin reuptake ligands to investigate serotonergic neuronal loss in these degenerative diseases.
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