title: N-fluoroalkylated and N-alkylated analogues of the dopaminergic D-2 receptor antagonist raclopride.
abstract: A series of raclopride [(S)-2-[(3,5-dichloro-6-methoxy-2- hydroxybenzamido)methyl]-1-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- (beta+, 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 Ki values 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.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, Missouri 63110.
authors.forename: G S
authors.initials: GS
authors.lastname: Lannoye
authors.forename: S M
authors.initials: SM
authors.lastname: Moerlein
authors.forename: D
authors.initials: D
authors.lastname: Parkinson
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D018492:Dopamine Antagonists; D005260:Female; D008024:Ligands; D008254:Macaca nemestrina; D008297:Male; D020891:Raclopride; D011854:Radiochemistry; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism; D012457:Salicylamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013134:Spiperone / Q000378:metabolism
chemical_list: D018492:Dopamine Antagonists; D008024:Ligands; D011954:Receptors, Dopamine; D012457:Salicylamides; D020891:Raclopride; D013134:Spiperone