N-Fluoroalkylated and N-Alkylated Analogues of the Dopaminergic D-2 Receptor Antagonist Raclopride

G. S. Lannoye, M. J. Welch, S. M. Moerlein, D. Parkinson

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23 Scopus citations


A series of raclopride [(S)-2-[(3,5-dichloro-6-methoxy-2-hydroxybenzamido)methyl]-l-ethylpyrrolidine] derivatives bearing pyrrolidino N-fluoroalkyl or -alkyl substituents were synthesized and evaluated as potential dopaminergic receptor-based positron tomography radiopharmaceuticals. Radiosynthetic procedures for producing the corresponding N-[18F]fluoroalkylated analogues of raclopride from 18F- (β+, t1/2 = 110 min) in high specific activity were also developed. In vitro binding assays using competitive displacement of [3H]spiperone from primate caudate tissue indicated that the N-alkylated analogues of raclopride had Kivalues of 5–40 nM, whereas the corresponding values for analogous N-fluoroalkylated derivatives ranged from 90–160 nM. The relatively low D-2 binding affinity of these fluorinated salicylamides was corroborated by in vivo tissue biodistribution results in rodents. On the basis of structure-binding correlations, the impact of intramolecular hydrogen bonding, ligand basicity, and steric bulk on the affinity of the benzamides for D-2 receptor binding are discussed. Strategies are presented for the development of alternative fluorinated salicylamides that are both receptor active and metabolically stable.

Original languageEnglish
Pages (from-to)2430-2437
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - 1990


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