Acute Inhibition of Cardiac Monoamine Oxidase A after Tobacco Smoke Inhalation: Validation Study of [11C]Befloxatone in Rats Followed by a Positron Emission Tomography Application in Baboons

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 314; no. 1; pp. 431 - 436
• Main Authors: Héric Valette, Michel Bottlaender, Frédéric DollÃ, Christine Coulon, Michèle Ottaviani, André Syrota
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.07.2005
• Subjects: Algorithms; Animals; Chromatography, High Pressure Liquid; Heart - diagnostic imaging; Injections, Intravenous; Isotope Labeling; Ligands; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - pharmacokinetics; Monoamine Oxidase Inhibitors - pharmacology; Myocardium - enzymology; Nicotiana; Nicotine - administration & dosage; Nicotine - pharmacology; Nicotinic Agonists - administration & dosage; Nicotinic Agonists - pharmacology; Oxazoles - chemical synthesis; Oxazoles - pharmacokinetics; Oxazoles - pharmacology; Papio; Positron-Emission Tomography; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Radiopharmaceuticals - pharmacology; Rats; Rats, Sprague-Dawley; Smoke - adverse effects; Sympathetic Nervous System - physiology; Tissue Distribution; Ventricular Function, Left - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.085704

The in vivo characteristics of [ 11 C]befloxatone were assessed in myocardium of rats and monkeys. A complete multicompartmental model was developed to quantify monkey cardiac monoamine oxidase A (MAO-A) binding sites using positron emission tomography (PET) and was applied to assess the acute effects of inhalation of tobacco smoke. Unknown compounds contained in tobacco smoke inhibit brain MAO. In vitro, befloxatone inhibits selectively, competitively, and reversibly MAO-A in human tissues. [ 11 C]Befloxatone (1.85 MBq) was i.v. injected into rats. Animals were sacrificed, dissected, and samples were assessed for radioactivity. Another group of rats was pretreated with clorgyline (10 mg/kg i.v.). Monkeys were injected with [ 11 C]befloxatone (222–370 MBq), and the chest was imaged with PET for 2 h. Presaturation and displacement experiments were performed using unlabeled befloxatone. For quantification of myocardial binding sites ( B max ), [ 11 C]befloxatone was first injected as a tracer dose (2.7–9.3 nmol) and 20 min later injected as a mixture of labeled and unlabeled befloxatone (labeled, 10.3–41.9 nmol; unlabeled, 407–765 nmol). In rodents, cardiac uptake was high (3.39 ± 0.5% injected dose/g tissue) and strongly inhibited (80%) by clorgyline. In monkeys, administration of unlabeled befloxatone displaced 85% of cardiac radioactivity. B max was found to be 208 ± 13 pmol ml -1 tissue. Inhalation of tobacco smoke decreased B max : 150 ± 6.2 pmol ml -1 , whereas nicotine did not. [ 11 C]Befloxatone allows a good visualization of the heart. Cardiac MAO-A B max was quantified and a clear effect of acute inhalation of tobacco smoke was evidenced. Therefore, a single cigarette can interfere with the cardiac turnover of catecholamines.