This investigation evaluates the efficacy of a 99mTc-labeled nitroimidazole (BMS-181321) in identifying oxygen-deprived tissue in two canine models of myocardial ischemia.
Methods: For both models (A and B), epicardial microvascular oxygen pressure (mPO2) was monitored by measuring the oxygen-dependent quenching of phosphorescence lifetime of Palladium mesotetra (4-carboxyphenyl) porphine. In Model A (beagles, n = 5), BMS-181321 was administered intravenously and a distal branch of the left anterior descending coronary artery (LAD) was ligated completely 40 sec later. Ten minutes later, the ligature was released establishing tissue reoxygenation. In Model B, flow through the LAD was reduced until the mPO2 was about 2 Torr. After bolus administration of BMS-181321 (50-60 mCi), coronary ischemia was continued for a residence period of up to 4 hr.
Results: With Model A, SPECT reconstructions revealed a small ischemic area in three of five dogs, however, a transmural accumulation of the compound was evident in the autoradiograms from all dogs. In the two animals in which the defect was not observed by SPECT, the ischemic episode had nominal effects on the ratio of +/- dp/dt (< 4% change as compared to baseline values). In Model B, SPECT reconstructions showed positive images of the oxygen-deprived area within the mid- to apical regions of the left ventricle (n = 5). Autoradiographic analysis showed a transmural association with cells resulting in an ischemic-to-nonischemic ratio of 3.5 +/- 0.4 (n = 4) for animals with similar residence times.
Conclusion: The results from both models suggest that BMS-181321 provides a noninvasive marker of regional ischemia in the heart and that this compound may have clinical utility for detection of coronary artery disease.