Targeting of Endothelin Receptors for Molecular Imaging of Atherosclerosis in Rabbits

Abstract

We wanted to determine whether a previously described in vivo accumulation of a ^99mTc-labeled endothelin derivative in atherosclerotic lesions is mediated by binding to endothelin receptors. Furthermore, the expression of endothelin receptors in atherosclerotic lesions of 2 different rabbit animal models for atherosclerosis was to be evaluated to determine whether endothelin receptors generally are a suitable target for atherosclerosis imaging. Methods: Normal vessels from untreated New Zealand White rabbits (NZW), balloon-denuded aortas from cholesterol-fed NZW, and atherosclerotic aortas from Watanabe Heritable Hyperlipidemic rabbits (WHHL) were used either as cross sections (cryosections) for receptor binding studies or for superfusion with a medium containing ¹²⁵I-labeled endothelin-1 or the ^99mTc-labeled endothelin derivative. Results: Cross sections of aortas from untreated NZW contained 45 ± 11.10⁶ endothelin A receptors per square millimeter and 55 ± 11.10⁶.endothelin B receptors per square millimeter, cross sections of balloon-denuded aortas from cholesterol-fed NZW contained 106 ± 16.10⁶ endothelin A receptors per square millimeter and 27 ± 16.10⁶ endothelin B receptors per square millimeter, and cross sections of atherosclerotic aortas from WHHL contained 40 ± 13.10⁶ endothelin A receptors per square millimeter and 5 ± 13.10⁶ endothelin B receptors per square millimeter. Balloon-denuded aortas from cholesterol-fed NZW (366 ± 132 amol.mm⁻², P < 0.001) and atherosclerotic aortas from WHHL (338 ± 175 amol.mm⁻², P < 0.002) accumulated significantly more of the ^99mTc-labeled endothelin derivative than did vessels from control animals (137 ± 26 amol.mm⁻²). On the contrary, ¹²⁵I-labeled endothelin-1–bound receptor mediated to superfused aortas from untreated NZW (12 ± 9 amol.mm⁻²) and to balloon-denuded aortas from cholesterol-fed NZW (19 ± 5 amol.mm⁻²) but not to aortas from WHHL. This lack of receptor-specific accumulation of ¹²⁵I-endothelin-1 in atherosclerotic areas of WHHL aortas, and this receptor-specific accumulation in atherosclerotic balloon-denuded NZW aortas that does not significantly increase in comparison with normal aortas of untreated NZW, cause failure of endothelins to detect atherosclerotic lesions. Conclusion: Although the density and the ratio of endothelin receptor subtypes change because of the development of atherosclerotic lesions in rabbit aortas, endothelin receptor targeting for imaging of atherosclerosis is not suitable.