Positron emission tomography (PET) studies of neuroreceptors hold great promise in determining the role of receptor defects in disease. Postsynaptic receptors have been a major focus of PET investigations to date, in large measure because appropriate postsynaptic radioligands are available for these purposes. Studies which determine presynaptic binding site changes will provide unique insights into the pathogenesis of diseases caused by selective neuronal cell losses. This application proposes to develop presynaptic radioligands which bind to the serotonin reuptake complex in the brain and, hence, will provide a non-invasive regional map of cerebral serotonergic innervation. The long-term goal of this research is the application of these radioligands to imaging studies of neurodegenerative diseases such as Alzheimer's and Parkinson's as well as to disorders such as depression, suicidal behavior, and obsessive compulsive disorders in which serotonergic dysfunctions are believed to play an important role. It is anticipated that the radioligands developed in this work will assist in the understanding of the evolution and clinical progression of these diseases and disorders. Recent studies by us have demonstrated that a radioiodinated derivative of 6-nitroquipazine ([I-125]-labeled 5-iodo-6-nitroquipazine) is a potent and selective radioligand for in vivo mapping of the presynaptic serotonin reuptake site. This radiotracer displays excellent in vivo properties which make it potentially valuable as a radiopharmaceutical for single photon emission computed tomography (SPECT) studies of regional serotonergic innervation when labeled with the I-123 radionuclide. The development of this compound for qualitative SPECT imaging studies will be continued in collaboration with researchers at the University of Pennsylvania and Lawrence Berkeley Laboratory. We have also demonstrated that the 5-fluoro derivative of 6nitroquipazine has a high affinity for the serotonin reuptake site. The primary goal of this proposal is to label 5fluoro-6-nitroquipazine (5-F-6-NQP) with fluorine- 18 (a short-lived positron emitter with a 110 min half-life) and to demonstrate the usefulness of this radiotracer for quantitative PET studies of serotonergic innervation. Tritium-labeled 5-F-6-NQP will be used to assess in vitro binding parameters as well as to determine the in vivo brain localization and the pharmacological profile of specific binding in control and serotonergic neurotoxintreated rats. High specific activity fluorine-1 8-labeled 5-F-6-NQP will be prepared and utilized in whole body distribution, regional brain localization, and metabolic stability studies in rats. Regional presynaptic serotonin reuptake site densities (B-max) and the equilibrium dissociation binding constant (K-d) for [F-18] 5-F-6-NQP will be determined in control and serotonergically impaired monkeys using PET and compartmental modeling. Pilot PET studies in control and Alzheimer's disease subjects are planned to demonstrate the usefulness of [F-18]5-F-6-NQP as a marker of serotonergic innervation in human subjects.
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