Targeting of Endothelin Receptors in the Healthy and Infarcted Rat Heart Using the PET Tracer¹⁸F-FBzBMS

Abstract

The endothelin subtype-A receptor (ET-A) is a promising therapeutic target in cardiovascular disease. We sought to determine the feasibility of an 18 F-labeled ligand, 18 F-(N-[[29-[[(4,5-dimethyl-3-isoxazolylimaging ET-A in the healthy and injured rat heart. Methods: Male Wistar rats were used for all experiments. The specificity of cardiac 18 F-FBzBMS uptake was determined in healthy animals (n 5 23) using pretreatment with various blocking agents and doses. Myocardial infarction (MI) was induced by permanent left coronary ligation in 32 animals. Autoradiography was conducted to determine regional FBzBMS distribution relative to tissue perfusion at various times after MI. Histology and immunohistochemistry were performed for validation. The feasibility of in vivo detection of the tracer signal was tested using dedicated small-animal PET (n 5 6). Results: At autoradiography, intravenous pretreatment with the selective ET-A blocker BMS-207940 reduced myocardial FBzBMS uptake by 93% 6 0.7%. Oral pretreatment with the clinical blocker bosentan resulted in a dose-dependent partial blockade (5 mg/kg, 48% 6 6%; 50 mg/kg, 61% 6 7%; and 100 mg/kg, 88% 6 0.7%). After MI, FBzBMS uptake was preserved in the infarct region from day 1 to month 6, whereas the perfusion tracer 201 Tl showed a persistent defect (MI-to-remote ratios: 201 Tl, 0.23 6 0.28, 0.39 6 0.07, 0.31 6 0.07, 0.24 6 0.12, 0.29 6 0.10, and 0.23 6 0.09; and FBzBMS, 0.94 6 0.28, 0.92 6 0.20, 0.88 6 0.13, 0.82 6 0.12, 0.80 6 0.11, and 0.84 6 0.08 at day 1, day 3, week 1, month 1, month 2, and month 6, respectively) (P , 0.01 vs. 201 Tl). Ex vivo analysis confirmed ET-A expression in the infarct area, where the signal was partially colocalized with CD31 expression on endothelial cells. In vivo small-animal PET successfully confirmed specific uptake and blockade of FBzBMS in healthy myocardium. Conclusion: Cardiac uptake of the PET tracer 18 F-FBzBMS is specific for ET-A expression in rats, shows infarct-related alterations, and can be imaged noninvasively. Further efforts to establish myocardial ET-A imaging methodology are warranted, with the perspective of determining role, efficacy, and benefit of ET-A targeted drug treatment in cardiovascular disease.

Radionuclide Imaging of Neurohormonal System of the Heart

“…The myocardial uptake of 18 F-FBzBMS was preserved in the infarct region from day 1 to month 6. Ex vivo analysis also confirmed ET A receptor expression in the infarct area, where PET imaging partially overlapping with CD31 expression on endothelial cells 91 .…”

Less Exploited GPCRs in Precision Medicine: Targets for Molecular Imaging and Theranostics

“…Besides its key physiological functions in particularly in the cardiovascular system, the ET axis also plays a major role in growth and progression of various tumors. To date, most of the efforts have been directed towards the development of radioactive receptor ligands for the visualization of endothelin receptor expression in vivo in cancer or in the heart [86,87,88,89,90,91,92].…”

Optical imaging probes and their potential contribution to radiotracer development

“…Based on non-peptidic, small molecular antagonists against either ET A R alone or ET A R and ET B R, there have been a number of developments (e.g. 18 F-SB209670, 11 C-Atrasentan, 18 F-FBzBMS or 18 F-PD156707) for the non-invasive in vivo imaging of ET receptor distribution, mainly for scintigraphic imaging (3,42,43,52,66,70).…”