NONINVASIVE DETECTION OF ATHEROSCLEROTIC LESIONS BY TC-99M-BASED IMMUNOSCINTIGRAPHIC TARGETING OF PROLIFERATING SMOOTH-MUSCLE CELLS

Background: Mouse/human chimeric antibody Z2D3 identifies an antigen p roduced exclusively by proliferating smooth muscle cells of human athe roma, and also cross reacts with experimentally induced atheroscleroti c lesions in rabbits. Fab' fragments of Z2D3 antibody were labeled wit h Tc-99m using glucaric acid as a weak transchelator. The potential ro le of Tc-99m-labeled Z2D3 scintigraphy was explored for noninvasive im aging of experimental atherosclerotic lesions. Methods and results: Tc -99m-Z2D3 Fab' was utilized for noninvasive imaging in four rabbits wi th experimentally induced atherosclerotic lesions and in one control r abbit. In addition, Tc-99m-labeled nonspecific 103D2 Fab' was used for comparison in four other rabbits with atherosclerotic lesions, The at herosclerotic lesions were induced by balloon de-endothelialization of the infradiaphragmatic abdominal aorta and 12 weeks of hyperlipidemic diet, An aliquot of 15 mCi (550 mBq) of Tc-99m pertechnetate was incu bated with 6.25 mg of glucaric acid for 30 min followed by incubation of Tc-99m glucarate with 375 mu g of Z2D3 Fab' or 103D2 Fab' for an ad ditional 30 min. Instant thin-layer chromatography demonstrated almost complete radiolabeling. Tc-99m-Z2D3 was administered IV and gamma ima ging was pet-formed at the time of injection, 3, 6, 9, and 12 h, follo wed by ex vivo imaging of the excised aorta, and biodistribution was p erformed. Unequivocal visualization of atherosclerotic lesions was pos sible in all four animals at 9 to 12 h with Z2D3 Fab', Quantitative up take, as represented by mean lesion-to-liver count density ratio, was 0.6+/-0.05. Imaging with nonspecific 103D2 Fab' did not show any local ization in the abdominal aorta (lesion-to-liver ratio, 0.45+/-0.02, p= 0.02). Ex rico lesion-to-normal aortic segment ratio was 4.3+/-0.9 for Z2D3 and 1.04+/-0.08 for nonspecific 103D2 Fab' (p=0.01). Biodistribu tion studies demonstrated 0.03+/-0.003% injected Z2D3 dose per gram in the atherosclerotic lesions as compared with 0.01+/-0.003% in the non denuded thoracic aorta of atherosclerotic rabbits (p=0.008). However, only 0.008+/-0.002% of the mean injected dose per gram was obtained in the atherosclerotic lesions (p=0.001) as compared with 0.005+/-0.003% in the normal aortic segments with 103D2. No Z2D3 uptake in normal ra bbits was observed on either the in vivo Or Cr vivo images. Conclusion s: The present study demonstrates that Tc-99m-based immunoimaging of t he vascular lesions may be feasible by the use of smaller antibody fra gments, Earlier visualization is possible at the expense of a lower ab solute antibody uptake in the lesions as compared to the use of intact antibody or larger fragments with longer circulating time.