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In Vivo Labeling of Endothelin Receptors with [¹¹C]L-753,037: Studies in Mice and a Dog

Sasa Aleksic, Zsolt Szabo, Ursula Scheffel, Hayden T. Ravert, William B. Mathews, Levente Kerenyi, Paige A. Rauseo, Raymond E. Gibson, H. Donald Burns and Robert F. Dannals

Division of Nuclear Medicine, Department of Radiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania

Endothelin (ET) is a potent mammalian vasoconstrictive peptide and a pressor agent. Its 3 isoforms, ET-1, ET-2, and ET-3, mediate several physiologic actions in several organ systems, binding to 2 major receptor subtypes: ET_A and ET_B. This study was undertaken to evaluate [¹¹C]L-753,037 [(+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxy-propyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno [1,2-ß]pyridine-6-carboxylate), a new mixed ET receptor A and B antagonist, as a tracer for in vivo labeling of ET receptors in mice and a dog. Methods: [¹¹C]L-753,037 was synthesized, purified, and formulated from a normethyl precursor, L-843,974, and [¹¹C]H₃I. The tracer was studied for its in vivo kinetics, biodistribution, and ET receptor binding characteristics in mice. In the dog, PET imaging was performed to evaluate binding of [¹¹C]L-753,037 to ET receptors in the heart. Specificity of binding was studied in the heart with the selective ET_A antagonist L-753,164. Results: Kinetic studies in mice showed highest tracer uptake at 5 min after injection in liver (25.0 percentage injected dose per gram [%ID/g]), kidneys (18.7 %ID/g), lungs (15.2 %ID/g), and heart (5.6 %ID/g). Initial high uptake in liver, lungs, and kidneys was followed by rapid washout during the next 10 min and a very slow clearance during the time of observation (2 h after injection). By contrast, the radioactivity in the heart remained constant over 2 h. Administration of both ET_A (L-753,164) and mixed ET_A/ET_B (L-753,137) receptor antagonists resulted in dose-dependent inhibition of [¹¹C]L-753,037 binding in mouse heart, lungs, and kidneys but not in the liver. Radioactivity in the brain was very low, indicating that the tracer does not cross the blood–brain barrier. In the dog, a dynamic PET study of the heart showed high tracer accumulation at 55–95 min after injection. Injection of L-753,164 at 30 min before [¹¹C]L-753,037 administration led to a significant reduction in tracer binding. [¹¹C]methyl triphenyl phosphonium was used as a tracer for reference images of the dog heart muscle. Conclusion: The results suggest that [¹¹C]L-753,037 binds to ET receptors in vivo and is, therefore, a promising candidate for investigation of these receptors and their occupancy by ET receptor antagonists using PET.

Key Words: endothelin receptors • PET • dogs

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