title: PET evaluation of the uptake of N-[11C]methyl CP-643,051, an NK1 receptor antagonist, in the living porcine brain.
abstract: Antagonists of neurokinin receptors such as CP-643,051 are presently under investigation as potential antidepressants, but little is known about the brain uptake and distribution of these agents. We developed a method for the efficient N-[11C]methylation of CP-122,721, yielding the NK1 antagonist N-[11C]methyl CP-643,051. The brain uptake and distribution of N-[11C]methyl CP-643,051 were studied by positron emission tomography (PET) in the anaesthetized pig, first in a baseline condition, and again after displacement of specific binding with the NK1 receptor antagonist L-732,138 (0.6 mg/kg, i.v.). In order to validate this displacement procedure, we tested the effects of L-732,138 on cerebral blood flow (CBF) in one pig. We found that N-[11C]methyl CP-643,051 had a distribution volume close to 3 ml g(-1), and a binding potential (pB) of 0.3 in the pig striatum; this binding was displaceable by the L-732,138 pre-treatment, which evoked a small (10-20%) global increase in CBF. We conclude that of N-[11C]methyl CP-643,051 may serve as a lead structure for the development of PET NK-1 ligands of higher specific binding in vivo.
authors.affiliation: PET Centre, Aarhus University Hospitals, Aarhus, Denmark. dirk@pet.auh.dk
authors.forename: D
authors.initials: D
authors.lastname: Bender
authors.forename: A K
authors.initials: AK
authors.lastname: Olsen
authors.forename: M K
authors.initials: MK
authors.lastname: Marthi
authors.forename: D F
authors.initials: DF
authors.lastname: Smith
authors.forename: P
authors.initials: P
authors.lastname: Cumming
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007091:Image Processing, Computer-Assisted; D009682:Magnetic Resonance Spectroscopy; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D013552:Swine; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C496681:3-(2-methoxy-5-trifluoromethoxybenzyl)amino-1-methyl-2-phenylpiperidine; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D019275:Radiopharmaceuticals; C086089:3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan; D014364:Tryptophan