Short-term pharmacokinetics and brain distribution of mecamylamine as a preliminary to carbon-11 labeling for nicotinic receptor investigation

• Published in: Journal of pharmaceutical sciences 2003-05, Vol.92 (5), p.1051-1057
• Main Authors: Debruyne, D., Sobrio, F., Hinschberger, A., Camsonne, R., Coquerel, A., Barré, L.
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive agents; Biological and medical sciences; Brain - metabolism; Carbon Radioisotopes; Cardiovascular system; Gas Chromatography-Mass Spectrometry; Injections, Intravenous; Isotope Labeling; Kidney - metabolism; Liver - metabolism; Lung - metabolism; Male; mecamylamine; Mecamylamine - blood; Mecamylamine - pharmacokinetics; Medical sciences; Myocardium - metabolism; Nicotinic Antagonists - blood; Nicotinic Antagonists - pharmacokinetics; nicotinic receptor; pharmacokinetics; Pharmacology. Drug treatments; Rats; Receptors, Nicotinic - metabolism; Tissue Distribution; Tomography, Emission-Computed - methods
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.10302

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 mecamylamine are suitable for experimental studies using 11C-radiolabeled mecamylamine preliminary to positron emission tomography (PET) in humans. An original gas chromatographic 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, 1.2h; clearance (CL), 1.2L/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 followed by a plateau after 15min. 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 making it a good candidate for carbon-11 labeling for experimental studies in view of final PET imaging.