A retrospect on the discovery of WAY-100635 and the prospect for improved 5-HT(1A) receptor PET radioligands.

Abstract. An outline is given of the developments that led to the identification of [O-methyl-(11)C]WAY-100635 (4) as the first useful PET ligand for imaging serotonin(1A) (5-HT(1A)) receptors in the living human brain. Recent attempts to develop 5-HT(1A) receptor radioligands superior to 4 are reviewed, and [carbonyl-(11)C]WAY-100635 (6) has been shown to be the best currently available radioligand for human studies. Of other (11)C-radiolabelled compounds, [O-methyl-(11)C](R,S)-CPC-222 (9), DWAY (8), and [(11)C]NAD-299 (14) all demonstrate specific binding to 5-HT(1A) receptors in animals and warrant further expedited studies in humans. The trans-fluorocyclohexane, 12, and fluorobenzene, [(18)F]p-MPPF 13, are highlighted as examples of promising (18)F-labelled ligands.