SEROTONIN 5-HT1A RADIOLIGANDS FOR PET

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The proposed research involves the development of radiopharmaceuticals which localize in discrete regions of the brain based upon their selective binding to serotonin 5-HT1A receptors. 5-HT1A receptors are believed to play a key role in the regulation of the serotonin system. Attempts to directly assess the nature of dysfunctions in this system in vivo in humans with depression and anxiety disorders have been limited to date by the lack of suitable radiopharmaceuticals. The goals of this work are to label various selective 5-HT1A ligands with the positron-emitting radionuclide 11C, to quantitate 5-HT1A receptor sites using positron emission tomography (PET) imaging in non-human primates, and to demonstrate their applicability in pilot human studies. Our plan is to develop selective and potent antagonist and agonist 5-HT1A radioligands for these purposes. The antagonist radioligand will be useful in quantitating the combined densities of both high and low affinity 5-HT1A receptors, and the agonist will be used to determine the regional concentrations of high affinity 5-HT1A receptors as well as to estimate regional endogenous serotonin concentrations in vivo. It is anticipated that the application of the proposed 5-HT1A radioligands, along with the concurrent use of a 5-HT2 antagonist radioligand (presently underway at the University of Pittsburgh PET Facility), will make possible the first direct assessments of changes in these serotonergic receptor systems in human subjects with antidepressant drug treatments. The 5-HT1A and 5-HT2 receptor systems have been the targets of antidepressant therapies for many years despite the lack of a definitive understanding of the adaptive changes associated with their success (or failure) in humans. The proposed studies will make available methods to directly investigate CNS serotonergic receptor changes as a result of antidepressant therapies in humans for the first time. Our specific aims include: 1) a thorough evaluation of the selective and potent 5-HT1A antagonist [11C]labeled WAY 100635 as a radioligand for PET imaging; 2) synthesis and evaluation of a high potency [11C]-labeled 5- HT1A agonist for in vivo measurements of the regional densities of the high affinity agonist state of these receptors; and 3) synthesis and evaluation of a lower potency [11C]-labeled 5-HT1A agonist for in vivo estimates of regional endogenous serotonin concentrations.