Short-Term Pharmacokinetics and Brain Distribution of Mecamylamine as a Preliminary to Carbon-11 Labeling for Nicotinic Receptor Investigation D. DEBRUYNE, 1,2 F. SOBRIO, 2 A. HINSCHBERGER, 1 R. CAMSONNE, 1,2 A. COQUEREL, 1,2 L. BARRE ´ 2 1 Laboratory of Pharmacology, CHU Co ˆ te de Nacre, 14032 Caen cedex, France 2 UMR–CEA/DSV, Centre CYCERON, Boulevard Becquerel, 14074 Caen cedex, France Received 8 April 2002; revised 25 June 2002; accepted 5 September 2002 ABSTRACT: As a preliminary to development and evaluation of labeled mecamylamine as a potential in vivo imaging ligand for human central nicotinic receptors (nAchRs), this work was intended to determine whether the pharmacokinetic properties of mecamy- lamine are suitable for experimental studies using 11 C-radiolabeled mecamylamine preliminary to positron emission tomography (PET) in humans. An original gas chro- matographic method for rapid and simple determination of mecamylamine in biological samples was developed and validated (within run precision, 3.8–5.2%; between assay variation, 5.3–6.9%; assay accuracy, 5.6–11.8%). The results of the pharmacokinetic investigation in the rat demonstrated a very fast clearance of mecamylamine from blood [half-life, 1.2 h; clearance (CL), 1.2 L/kg/h) concomitant with an uptake that was higher in kidney, intermediate in lung, and lower in heart, liver, and brain. Brain tissue kinetics of mecamylamine showed a similar pattern for all the regions, with a rapid increase fol- lowed by a plateau after 15 min. This plateau differed according to the region of the brain; it was higher in colliculi, hippocampus, and cortex (area of high density of nAchRs) than in cerebellum or white matter (area with a limited population of nAchRs). No other lipophilic metabolites that were able to disturb the specific binding to nAchRs were identified during the investigation. Thus, mecamylamine shows peculiar qualities mak- ing it a good candidate for carbon-11 labeling for experimental studies in view of final PET imaging. ß 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:1051–1057, 2003 Keywords: mecamylamine; nicotinic receptor; pharmacokinetics INTRODUCTION Positron emission tomography (PET) offers the possibility to monitor human central nicotinic receptors (nAchRs) in a variety of central nervous disorders,includingnicotinicaddiction,Parkinson’s and Alzheimer’s diseases, and Tourrette’s syn- drome. 1,2 These receptors are part of the super- family of neurotransmitter-gated ion channels that are responsible for rapid intracellular com- munication. 3 The nAchRs have agonist/com- petitive antagonist binding sites of low and high affinity located near the membrane surface and binding sites for noncompetitive ion channel blockers. 4,5 To date, the only tracer available for human PET studies is [ 11 C]nicotine, which is not a sui- table tracer for PET studies of nAchRs in the human brain. 6 Novel nAchRs ligands, such as 18 F-labeled derivatives of epibatidine or pyridyl ether analogs labeled with 18 F, 76 Br, or 11 C, were JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 5, MAY 2003 1051 Correspondence to: D. Debruyne (Telephone: 02-31-06-46- 71; Fax: 02-31-06-46-73; E-mail: debruyne-d@chu-caen.fr) Journal of Pharmaceutical Sciences, Vol. 92, 1051–1057 (2003) ß 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association