Date of Award

Summer 8-2010

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biomedical Engineering

First Advisor

Said Audi

Second Advisor

Anne Clough

Third Advisor

Ming Zhao

Abstract

Myocardial infarction (MI) is a condition in which blood supply to the heart is insufficient. MI is associated with two forms of cell death: apoptosis and necrosis. 99mTc-duramycin (99mTc-D) is a novel radiopharmaceutical that detects cell death by recognizing externalized phosphatidylethanolamine. The objective of this study was to develop a compartmental model for 99mTc-D uptake kinetics in normal and infarct myocardium, and utilize this model to compare the uptake kinetics of 99mTc-D in MI with that of another radiopharmaceutical, 99mTc-C2A-GST.

MI was induced in rats which were then injected (i.v.) with 99mTc-D. Rats were sacrificed at 3, 10, 20, 60, and 180 minutes after injection. Normal and infarct myocardial tissue were weighed and measured for tracer uptake by gamma counting. 99mTc-D blood clearance data was also recorded by drawing blood samples at different time points after injection. Results show that 99mTc-D is sequestered in MI, but not in normal myocardium, that the uptake of 99mTc-D in MI is 48% higher than for 99mTc-C2A-GST, and that the blood clearance rate for 99mTc-D is faster than for 99mTc-C2A-GST.

We evaluated the ability of three compartmental models, with different assumptions regarding 99mTc-D uptake kinetics in MI, to interpret the uptake data of 99mTc-D in normal and infarct myocardium. Model 2, which assumes saturable intracellular probe binding kinetics, and Model 3, which assumes saturable vascular and intracellular probe binding kinetics, provided reasonable fits to 99mTc-D uptake data that were not different. Both models suggested a ~3-fold larger number of available binding sites for 99mTc-D as compared to 99mTc-C2A-GST. This is consistent with the fact that phosphatidylethanolamine (99mTc-D binding target) accounts for ~20% of all phospholipids in mammalian cellular membranes as compared to ~7% for phosphatidylethanolamine and phosphatidylserine (99mTc-C2A-GST binding target) combined. Thus, 99mTc-D and 99mTc-C2A-GST appear to detect a consistent level of cell death in the same MI model. Models 2 and 3 differed in terms of the contribution of the smaller molecular weight of 99mTc-D as compared to 99mTc-C2A-GST to 99mTc-D greater uptake in MI. The results of this study provide a basis for quantitative interpretation of 99mTc-D in vivo uptake in MI.