Delineation of hypoxia in canine myocardium using PET and copper(II)-diacetyl-bis(N⁴-methylthiosemicarbazone)

Copper(II)-diacetyl-bis(N⁴-methylthiosemicarbazone) (copper-ATSM) is a hypoxia-avid tracer for the selective identification of hypoxic tissue. Using canine models of hypoxic myocardium, we report our findings on *Cu-ATSM PET (*Cu is defined as either ⁶⁰Cu, ⁶¹Cu, or ⁶⁴Cu) for the delineation of ischemic and hypoxic myocardium. Methods: In protocol I, myocardial hypoxia was induced by global hypoxia (n = 3). In protocol II, myocardial ischemia was generated by occlusion of the left anterior descending coronary artery (n = 9). In protocol III, coronary artery stenosis was induced by a stenosis in the left anterior descending coronary artery (n = 4). PET dynamic data were acquired immediately after tracer injection. Tracer retention kinetics were analyzed using either monoexponential analysis (1/k_mono) or a simple 2-compartment model (1/k₄). Results: In protocol I, tracer retention in hypoxic myocardium was 2-fold greater than in normal myocardium, despite a 7-fold increase in blood flow (normal, 0.70 ± 0.42 mL·min^-1·g^-1; hypoxic, 4.94 ± 3.00 mL·min^-1·g^-1 [P < 0.005]). In protocol II, ∼3 h after occlusion, retention of *Cu-ATSM within 20 min was greater in ischemic regions (myocardial blood flow, 0.28 ± 0.26 mL·min^-1·g^-1) than in normal tissue (myocardial blood flow, 0.52 ± 0.19 mL·min^-1·g^-1) (1/k_mono, 40.72 ± 39.0 min vs. 26.69 ± 22.29 min [P < 0.05]; 1/k₄, 6.85 ± 4.90 min vs. 3.51 ± 1.97 min [P < 0.05]). In selected dogs, tracer retention decreased at 24 h, suggesting the development of necrosis with no subsequent retention of *Cu-ATSM. In protocol III, dobutamine infusion after stenosis placement resulted in increased tracer retention consistent with hypoxia in the damaged regions. Conclusion: *Cu-ATSM PET has shown quantitative selective uptake in hypoxic myocardium within 20 min of tracer administration in 3 canine models of hypoxia.