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

• Published in: The Journal of nuclear medicine (1978) Vol. 42; no. 8; pp. 1274 - 1280
• Main Authors: Aleksic, Sasa, Szabo, Zsolt, Scheffel, Ursula, Ravert, Hayden T, Mathews, William B, Kerenyi, Levente, Rauseo, Paige A, Gibson, Raymond E, Burns, H. Donald, Dannals, Robert F
• Format: Journal Article
• Language: English
• Published: Reston, VA Soc Nuclear Med 01-08-2001; Society of Nuclear Medicine
• Subjects: Animals; Biological and medical sciences; Contrast media. Radiopharmaceuticals; Dogs; Endothelin Receptor Antagonists; Investigative techniques, diagnostic techniques (general aspects); Isotope Labeling; Medical sciences; Mice; Miscellaneous. Technology; Pharmacology. Drug treatments; Pyridines - pharmacokinetics; Radionuclide investigations; Radiopharmaceuticals; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin - metabolism; Species Specificity; Tissue Distribution; Tomography, Emission-Computed; Radionuclide study; Fissipedia; Evaluation; Animal model; Carnivora; Endothelin; Radiolabelling; Rodentia; Experimental study; In vivo; Vertebrata; Mammalia; Mouse; Animal; Pharmacokinetics; Radiopharmaceuticals; Dog; Medical application; Positron; Emission tomography
• ISSN: 0161-5505; 1535-5667

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 [(11)C]L-753,037 [(+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxy-propyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno [1,2-beta]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.
[(11)C]L-753,037 was synthesized, purified, and formulated from a normethyl precursor, L-843,974, and [(11)C]H(3)I. 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 [(11)C]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.
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 [(11)C]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 [(11)C]L-753,037 administration led to a significant reduction in tracer binding. [(11)C]methyl triphenyl phosphonium was used as a tracer for reference images of the dog heart muscle.
The results suggest that [(11)C]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.