Technetium-99m-nitroimadazole uptake in a swine model of demand ischemia

Nitroheterocycles are electron affinic, lipophilic compounds that are retained in hypoxic tissue. This study was designed to test the hypothesis that 99mTc-5-oxa-amine-oxime nitroimadazole (BMS-194796) is retained in ischemic myocardial tissue in a swine model of demand ischemia and that the retained tracer can be imaged in vivo.

Eighteen domestic swine were anesthetized, intubated and instrumented, including placement of a stenois (80% narrowing) mounted on a catheter into the left anterior descending (LAD) coronary artery. Twelve experiments had complete sets of data for analysis. Each animal was paced at about 200 bpm for 4 min, and 28 mCi of 99mTc BMS-194796 were injected during the last minute of pacing. Dynamic planar imaging was started after pacing and completed at 2.5 hr. In the last 8 experiments, SPECT imaging was performed after planar imaging and completed 3.5 hr after injection. Hemodynamic measurements were made continuously. Blood flow by microspheres and myocardial lactate extraction were measured at control, during pacing and after 2 hr of recovery. The animals were then killed; the risk region was delineated and the hearts were removed, sliced, imaged and stained with triphenyl tetrazolium chloride.

Nine of the 12 animals became ischemic (net lactate production) during pacing; 3 did not. None of the 3 nonischemic experiments showed focal uptake on ex vivo or in vivo imaging. All 9 of the ischemic experiments showed focal BMS uptake in the risk region on ex vivo imaged slices; 6 of 9 had uptake in the risk region on in vivo imaging; and 4 of these 6 had small scattered areas of subendocardial necrosis in the risk region on triphenyl tetrazolium chloride staining. Four animals had small infarcts in the distribution of proximal LAD branch vessels occluded by the stenosis catheter. All animals with branch vessel infarcts had positive in vivo images. Overall, 8 of 9 ischemic experiments had positive in vivo images.

These data support the conclusion that focal myocardial retention of BMS-194796 can be visualized on in vivo imaging in closed chest large animal model after intravenous injection.