Quantitative analysis of [^99mTc]C2A-GST distribution in the area at risk after myocardial ischemia and reperfusion using a compartmental model

Objective: It was recently demonstrated that the radiolabeled C2A domain of synaptotagmin I accumulates avidly in the area at risk after ischemia and reperfusion. The objective was to quantitatively characterize the dynamic uptake of radiolabeled C2A in normal and ischemically injured myocardia using a compartmental model. Methods: To induce acute myocardial infarction, the left descending coronary artery was ligated for 18 min, followed by reperfusion. [^99mTc]C2A-GST or its inactivated form, [^99mTc]C2A-GST-NHS, was injected intravenously at 2 h after reperfusion. A group of four rats was sacrificed at 10, 30, 60 and 180 after injection. Uptake of [^99mTc]C2A-GST and [^99mTc]C2A-GST-NHS in the area at risk and in the normal myocardium were determined by gamma counting. A compartmental model was developed to quantitatively interpret myocardial uptake kinetic data. The model consists of two physical spaces (vascular space and tissue space), with plasma activity as input. The model allows for [^99mTc]C2A-GST and [^99mTc]C2A-GST-NHS diffusion between vascular and tissue spaces, as well as for [^99mTc]C2A-GST sequestration in vascular and tissue spaces via specific binding. Results: [^99mTc]C2A-GST uptake in the area at risk was significantly higher than that for [^99mTc]C2A-GST-NHS at all time points. The compartmental model separated [^99mTc]C2A-GST uptake in the area at risk due to passive retention from that due to specific binding. The maximum amount of [^99mTc]C2A-GST that could be sequestered in the area at risk due to specific binding was estimated at a total of 0.048 nmol/g tissue. The rate of [^99mTc]C2A-GST sequestration within the tissue space of the area at risk was 0.012 ml/min. Modeling results also revealed that the diffusion rate of radiotracer between vascular and tissue spaces is the limiting factor of [^99mTc]C2A-GST sequestration within the tissue space of the area at risk. Conclusion: [^99mTc]C2A-GST is sequestered in the ischemically injured myocardium in a well-defined dynamic profile. Model parameters will be valuable indicators for gauging and guiding the development of future-generation molecular probes.