Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D4 Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET

Abstract

A series of fluoro-substituted analogs structurally derived from the aminomethyl-substituted pyrazolo[1,5- a]pyridine lead compounds 9 (FAUC 113) and 10 (FAUC 213) were synthesized and evaluated as high-affinity D 4 receptor (D 4R) ligands ( 3a- 3h, K i = 1.3-28 nM). The para-fluoroethoxy-substituted derivatives 3f and 3h revealed an outstanding D 4 subtype selectivity of more than 3 orders of magnitude over both congeners D 2 and D 3 combined with inverse agonism at D 4R. The corresponding (18)F-labeled radioligands revealed high serum stability in vitro and log P values of 2-3. In vitro rat brain autoradiography showed specific binding of [ (18)F]3h in distinct brain regions, including the gyrus dentate of the hippocampus, that were inhibited by both eticlopride (65-80%) and the selective D 4R antagonist 10 (78-93%). The observed binding pattern was mainly consistent with the known D 4R distribution in the rat brain. Thus, [(18)F]3h (FAUC F41) represents a potential radioligand for studying the D 4R in vivo by positron emission tomography (PET).