[3H]1-(cyclopropylmethyl)-4-(2-(4-fluorophenyl)-2-oxoethyl) piperidine HBr (DuP 734). A selective ligand for sigma receptors in mouse brain in vivo.
1-(Cyclopropylmethyl)-4-(2-(4-fluorophenyl)-2-oxoethyl) piperidine HBr (DuP 734) is a novel sigma receptor ligand which exhibits promise in preclinical animal models as an antipsychotic agent without motor side effects. In vitro and in vivo receptor binding profiles of DuP 734 in mouse brain using [3H]DuP 734 and [3H]N-allylnormetazocine ((+)-SKF 10,047) were studied. The pharmacology and stereospecificity of [3H]DuP 734-labeled sites in mouse brain, both in vitro and in vivo, was consistent with sigma receptor pharmacology. Specific in vivo binding of [3H]DuP 734 in brain peaked 1 hr after i.v. injection and this level of binding was maintained up to 4 hr. On the other hand, plasma concentration of [3H]DuP 734 decreased rapidly within 20 min after injection, indicating different pharmacokinetics between brain and plasma levels. Nonspecific binding, defined using 1 mg/kg (2.66 mumol/kg) of haloperidol, was approximately 30% of total binding 1 hr after injection of radiotracer. Administration of DuP 734 potently antagonized the binding of [3H]DuP 734 and [3H](+)-SKF 10,047 to brain sigma receptors in vivo with ID50 values of 0.02 and 0.07 mg/kg (0.07 and 0.25 mumol/kg), respectively. However, (+)-SKF 10,047, which possess a high affinity (IC50 = 22.5 nM) for [3H]DuP 734 binding in vitro, failed to displace [3H]DuP 734 binding in vivo. Thus in vitro receptor binding data may not predict in vivo receptor occupancy. Overall, the data suggest [3H] DuP 734 is a good ligand for in vivo imaging of sigma receptors.
Central Nervous System Diseases Research, DuPont Merck Pharmaceutical Company, Wilmington, Delaware.
M
M
Watanabe
D
D
Rominger
S D
SD
Hurt
E B
EB
De Souza
S W
SW
Tam
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010620:Phenazocine / Q000031:analogs & derivatives / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D017480:Receptors, sigma / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D014316:Tritium
D010880:Piperidines; D017480:Receptors, sigma; D012702:Serotonin Antagonists; D014316:Tritium; C012134:SK&F 10047; C078773:DuP 734; D010620:Phenazocine