Targeting of endothelin receptors for molecular imaging of atherosclerosis in rabbits.
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.


CONCLUSIONS
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.
Meding
Jörg
J
Institut für Diagnostikforschung GmbH, Berlin, Germany. j.meding@dkfz.de
Dinkelborg
Ludger M
LM
Grieshaber
Manfred K
MK
Semmler
Wolfhard
W
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001161:Arteriosclerosis / Q000000981:diagnostic imaging* / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D019333:Endothelin-2 / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D011817:Rabbits; D011877:Radionuclide Imaging; D017466:Receptors, Endothelin / Q000378:metabolism*; D013667:Technetium
D019332:Endothelin-1; D019333:Endothelin-2; D007457:Iodine Radioisotopes; D017466:Receptors, Endothelin; D013667:Technetium