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

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(4)R) 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(4)R. 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(4)R antagonist 10 (78-93%). The observed binding pattern was mainly consistent with the known D(4)R distribution in the rat brain. Thus, [(18)F]3h (FAUC F41) represents a potential radioligand for studying the D(4)R in vivo by positron emission tomography (PET).