PET evaluation of the uptake of N-[11C]methyl CP-643,051, an NK1 receptor antagonist, in the living porcine brain.

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. Copyright 2004 Elsevier Inc.