THERAPY AND PREVENTION RECEPTOR LOCALIZATION Peripheral-type benzodiazepine receptors in the living heart characterized by positron emission tomography

The presence of specific benzodiazepine binding sites in the hearts of dogs and human beings was demonstrated in vivo by a noninvasive method, positron emission tomography (PET). An antagonist of the peripheral-type benzodiazepine binding site, PK 1 1 195, was labeled with carbon1 1, a short-lived positron emitter. When injected at high specific activity, 1C-PK l 1195 was concentrated in the myocardium. As increasing amounts of unlabeled PK 11195 were added to the radioactive ligand, the myocardial ligand concentration was proportional to myocardial regional perfusion up to quantities of 40 nmol/kg body weight. Above 40 nmol/kg the ligand concentration reached a maximum value (6000 pmol/cm3), which could be considered as the total number of binding sites per unit heart volume. The specificity of 1 'C-PK 11195 binding to canine heart was demonstrated from a study on the inhibition of binding for radioligand by an excess of several agonists or antagonists of benzodiazepine receptor. The distribution and specificity of 1 1C-PK 11 195 was similar in dogs and in human beings. PET thus opens the way to the investigation of the peripheral-type benzodiazepine receptor in a clinical situation, since it has recently been shown that this receptor could be coupled to the calcium channel in the heart. Circulation 73, No. 3, 476-483, 1986. SHORTLY AFTER the discovery of benzodiazepine binding sites in the central nervous system,'-4 specific high-affinity binding sites were also demonstrated in peripheral organs such as the kidney, liver, skeletal and ileal muscle, lungs, and heart.5-7 However, the ligand specificity and affinity for the peripheral-type binding site is completely different from that of the central-type site.' 9 It was found recently that a compound with a nonbenzodiazepine structure, 1-(2-chlorophenyl)N-methyl N-( 1 -methylpropyl)-3-isoquinolinecarboxamide (PK 11195), is very potent in the binding inhibition of ligands such as 3H-RO 5-4864, known to bind with high affinity to peripheral-type sites. 1O12 In the heart, in vitro and in vivo, PK 11195 was even more potent than RO 5-4864. Furthermore, it has been shown that peripheral-type benzodiazepine From the Service Hospitalier Fred&ric Joliot, Ddpartment de Biologie. Commissariat a l'Energie Atomique, Orsay; Service de Rdanimation Medicale, Caen; and INSERM U 13, H6pital Claude-Bernard, Paris, France. Address for correspondence: Andre Syrota, M.D., Ph.D., Service Hospitalier Freddric Joliot, 91406 Orsay, France. Received July 12, 1985; revision accepted Nov. 15, 1985. 476 binding sites are pharmacologic receptors coupled to calcium channels in guinea pig papillary muscle'3 and that PK 1 1 195, a compound devoid of activity in heart muscle, is an antagonist of the peripheral-type benzodiazepine receptor. It thus seemed interesting to characterize the peripheral-type benzodiazepine receptor noninvasively in vivo in the canine and human heart with PK 11195 as ligand. Noninvasive investigation of cardiac receptors was impossible until the introduction of labeling methods using carbon11, a short-lived cyclotron isotope, and of positron emission tomography (PET). PET is a vizualization technique that permits quantitative measurements in vivo of local perfusion, metabolism, pharmacology, and biochemistry in the heart by external detection. 14' 15 It thus offers the possibility of characterizing changes in receptor binding properties as well as regional receptor density in the hearts of intact animals and ultimately in human cardiac diseases. 16 17 We report here a first attempt to characterize the peripheral-type benzodiazepine receptor in the canine and human heart by PET and "C-PK 11195. CIRCULATION by gest on N ovem er 8, 2017 http://ciajournals.org/ D ow nladed from THERAPY AND PREVENTION-RECEPTOR LOCALIZATION