TY - JOUR
T1 - In vivo labeling of endothelin receptors with [11C]L-753,037
T2 - Studies in mice and a dog
AU - Aleksic, S.
AU - Szabo, Z.
AU - Scheffel, U.
AU - Ravert, H. T.
AU - Mathews, W. B.
AU - Kerenyi, L.
AU - Rauseo, P. A.
AU - Gibson, R. E.
AU - Burns, H. D.
AU - Dannals, R. F.
PY - 2001/8/16
Y1 - 2001/8/16
N2 - 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: ETA and ETB. 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-β]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]H3l. 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 ETA 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 ETA (L-753,164) and mixed ETA/ETB (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.
AB - 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: ETA and ETB. 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-β]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]H3l. 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 ETA 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 ETA (L-753,164) and mixed ETA/ETB (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.
KW - Dogs
KW - Endothelin receptors
KW - PET
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M3 - Article
C2 - 11483691
AN - SCOPUS:0034898740
SN - 0161-5505
VL - 42
SP - 1274
EP - 1280
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 8
ER -