Targeting of endothelin receptors for molecular imaging of atherosclerosis in rabbits
Jörg Meding1, Ludger M Dinkelborg, Manfred K Grieshaber
1Institut für Diagnostikforschung GmbH, Berlin, Germany. j.meding@dkfz.de
Unlabelled:
We wanted to determine whether a previously described in vivo accumulation of a (99m)Tc-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 (125)I-labeled endothelin-1 or the (99m)Tc-labeled endothelin derivative.
Results:
Cross sections of aortas from untreated NZW contained 45 +/- 11.10(6) endothelin A receptors per square millimeter and 55 +/-11.10(6).endothelin B receptors per square millimeter, cross sections of balloon-denuded aortas from cholesterol-fed NZW contained 106 +/- 16.10(6) endothelin A receptors per square millimeter and 27 +/- 16.10(6) endothelin B receptors per square millimeter, and cross sections of atherosclerotic aortas from WHHL contained 40 +/- 13.10(6) endothelin A receptors per square millimeter and 5 +/- 13.10(6) 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 (99m)Tc-labeled endothelin derivative than did vessels from control animals (137 +/- 26 amol.mm(-2)). On the contrary, (125)I-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 (125)I-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.
Insights
Endothelin receptor targeting is not suitable for imaging atherosclerosis, as radiolabeled endothelin derivatives do not specifically accumulate in atherosclerotic lesions. Studies in rabbit models showed inconsistent binding, failing to detect disease progression effectively.
Area of Science:
- Cardiovascular Research
- Medical Imaging
- Pharmacology
Background:
- Atherosclerosis is a chronic inflammatory disease characterized by plaque buildup in arteries.
- Endothelin receptors are implicated in vascular function and disease.
- Previous studies suggested potential for radiolabeled endothelin derivatives in atherosclerosis imaging.
Purpose of the Study:
- To determine if in vivo accumulation of a (99m)Tc-labeled endothelin derivative in atherosclerotic lesions is receptor-mediated.
- To evaluate endothelin receptor expression in rabbit models of atherosclerosis.
- To assess the suitability of endothelin receptors as targets for atherosclerosis imaging.
Main Methods:
- Utilized New Zealand White (NZW) and Watanabe Heritable Hyperlipidemic (WHHL) rabbits.
- Examined normal, balloon-denuded, and atherosclerotic aortas.
- Performed receptor binding studies using cryosections.
- Conducted superfusion experiments with (125)I-labeled endothelin-1 and a (99m)Tc-labeled endothelin derivative.
Main Results:
- Endothelin receptor A and B densities varied across different aortic conditions and rabbit models.
- (99m)Tc-labeled endothelin derivative accumulation was significantly higher in balloon-denuded NZW and WHHL aortas compared to controls.
- (125)I-labeled endothelin-1 showed receptor-mediated binding in untreated and balloon-denuded NZW aortas but not in WHHL aortas.
- Lack of specific endothelin-1 binding in WHHL lesions and non-significant increase in NZW lesions indicated failure to detect atherosclerosis.
Conclusions:
- Endothelin receptor subtype density and ratios change during atherosclerosis development in rabbit aortas.
- Despite these changes, endothelin receptor targeting is not a suitable strategy for imaging atherosclerosis.
- The investigated radiolabeled endothelin derivative did not demonstrate reliable targeting for diagnostic purposes.
