Synthesis and in Vitro Evaluation of 2,3-Dimethoxy-5-(fluoroalkyl)-Substituted Benzamides: High-Affinity Ligands for CNS Dopamine D₂ Receptors

A number of 2,3-dimethoxy-5-(fluoroalkyl)-N-[(l-ethyl-2-pyrrolidinyl)methyl]benzamides (with or without a 6-hydroxy group) were synthesized and evaluated as dopamine D₂ receptor ligands. The parent acids were synthesized via the Claisen rearrangement of the appropriate O-allyl ethers, which were derived from o-vanillic acid or 2,3-di- methoxysalicylic acid. A decrease in reactivity was found to be characteristic of pentasubstituted benzoates, and difficulties were encountered with the introduction of fluorine onto the ethyl side chains. The (fluoroethyl)- and (fluoropropyl)salicylamides were 5 times more potent than the corresponding benzamides in inhibiting [³H]spiperone binding to the D₂ receptor. These (fluoroalkyl)salicylamides are of potential value for in vivo positron emission tomography (PET) studies upon the basis of their relatively selective, high potency binding affinity for the D₂ receptor.