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.
The in vivo characteristics of [11C]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. [11C]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 [11C]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 (Bmax), [11C]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. Bmax was found to be 208 +/- 13 pmol ml(-1) tissue. Inhalation of tobacco smoke decreased Bmax: 150 +/- 6.2 pmol ml(-1), whereas nicotine did not. [11C]Befloxatone allows a good visualization of the heart. Cardiac MAO-A Bmax 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.
Valette
Héric
H
Service Hospitalier Frédéric Joliot, DSV/DRM-CEA, French Atomic Agency, F-91406 Orsay, France. valette@shfj.cea.fr
Bottlaender
Michel
M
Dollé
Frédéric
F
Coulon
Christine
C
Ottaviani
Michèle
M
Syrota
André
A
D000465:Algorithms; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006321:Heart / Q000000981:diagnostic imaging; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008024:Ligands; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology*; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D010215:Papio; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012906:Smoke / Q000009:adverse effects*; D013564:Sympathetic Nervous System / Q000502:physiology; D014018:Tissue Distribution; D016277:Ventricular Function, Left / Q000187:drug effects
D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D018722:Nicotinic Agonists; D010080:Oxazoles; D019275:Radiopharmaceuticals; D012906:Smoke; C090014:befloxatone; D009538:Nicotine; D008995:Monoamine Oxidase