This Phase I proposal describes a collaborative program that will synthesize a series of compounds related to (S)-5-F-8-hydroxy-2- (dipropylamino)tetralin [(S)-UH-301], an antagonist of the serotonin 5HT1A receptor. Recently RBI has developed a procedure for the efficient synthesis of (S)-UH-301 that makes it feasible to envision the synthesis of analogs and derivatives described in this proposal. In particular we propose 3 major activities during the initial 6 month feasibility study. First, [3H]-UH-301 will be synthesized and tested for its ability to label the 5HT1A receptor expressed at high level in HeLa cells. Second, we propose to develop a photoaffinity ligand based on the N-p-azido- phenethyl analog of (S)-UH-301 and determine if the molecule can photolabel the 5HT1A receptor stably expressed at high level in HeLa cells. We will then establish if the compound can be used to photolabel 5HT1A receptors in the brain. Third, we propose to synthesize a biotinylated analog of the p-amino-phenethyl analog of (S)-UH-301 and determine if it can be used to affinity purify 5HT1A receptors expressed at high level in cells. In Phase II, we anticipate fully characterizing the activity of the active molecules synthesized in Phase I. We will characterize the specificity of [3H]-UH-301, the photoaffinity probe and the affinity probe by testing them in binding assays for other 5HT receptors (as well as receptors for other biogenic amines). We will attempt to increase the specific activity of the radiolabeled derivative of (S)-UH-301 by incorporation of [125-I] into a congener. If desirable, we will synthesize additional derivatives in an attempt to enhance the specificity and affinity towards the 5HT1A receptor.