In vivo labeling of angiotensin II receptors with a carbon-11-labeled selective nonpeptide antagonist

Angiotensin II (ANG II) initiates a variety of physiological effects by binding to high affinity receptors. Two ANG II receptor subtypes, AT1 and AT2, have recently been identified. This study was undertaken to evaluate [¹¹C]L-159,884, an AT1 subtype selective nonpeptide antagonist, as a potential PET tracer. Methods: Carbon-11-L-159,884 was prepared by alkylation of the nor precursor with [¹¹C]methyliodide and was studied for its in vivo binding characteristics, biodistribution and kinetics in mice. The effects of PD-123319, an AT2-selective ANGII antagonist, as well as those of alpha- and beta-adrenergic drugs on [¹¹C]L-159,884 binding were investigated also. Results: Administration of the AT1 antagonists resulted in dose-dependent inhibition of [¹¹C]L-159,884 binding in the kidneys, the organ with the highest density of AT1 receptors. Inhibition was also observed in the lungs and the heart. Adrenergic drugs did not influence [¹¹C]L-159,884 binding to AT1 receptors. Kinetic studies showed rapid tracer uptake in the liver, kidneys, lungs and heart. Excretion of the radioactivity occurred primarily through the intestinal tract (>29% in 90 min), with less than 8% excreted through the urine. Conclusion: The results suggest that [¹¹C]L-159,884 binds in vivo to AT1 receptors in mouse kidneys, lungs and heart. This radiotracer appears to be a promising candidate for studying ANG II receptors in vivo by PET.