Visualization of Dynamic Expression of Myocardial Sigma-1 Receptor after Myocardial Ischemia and Reperfusion using I-125iodophenyl-piperidino-cyclopenntanon(OI5V) imaging

1382 Objectives: Sigma receptors were first reported in the central nervous system in 1976, and as one of then Sigma-1 receptor (Sig-1R) was cloned in 1996. Sig-1R has been shown to relate many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, psychiatric disorders, etc. Sig-1R is mainly an endoplasmic reticulum protein that resides specifically at the mitochondria-associated endoplasmic reticulum membrane and suggested to act a pluripotent modulator. It is reported recently that Sig-1R expresses in cardiomyocytes as a molecular chaperon and functions based on interaction with various proteins and may be activated when living system is under abnormal state. Therefore, we aimed to image Sig-1R and explore how myocardial ischemia and reperfusion affect myocardial Sig-1R expression. Methods: The left coronary artery (LCA) was occluded for 30-min followed by reperfusion for 3, 7, 14 days, and 1 month. Then, Sig-1R imaging tracer, I-125-iodophenyl-piperidino-cyclopenntanon (OI5V) (1.5MBq) was injected at 30 min before sacrifice. Just before sacrifice, LCA was reoccluded and Tc-MIBI (150-180MBq) was injected to verify the area at risk. Then, dual-tracer autoradiography of the left ventricular short axis slices was performed. The first autoradiographic exposure on an imaging plate was performed for 10-15 min to visualize the area at risk expressed by Tc-99m-MIBI distribution at 1 to 2 h after sacrifice. Three days later the second exposure was made for 4 days to visualize the I-125-OI5V uptake. The OI5V uptake ratio in an ischemic area was calculated by dividing the count density in an ischemic area by that of a normally perfused area. In vivo blocking study was performed to reveal binding selectivity of OI5V to Sig-1R. Results: One day after reperfusion, no significant OI5V uptake was observed in both normally perfused area and area at risk (OI5V uptake ratio was 0.90 ± 0.12). However, at day 3, intense uptake was observed inhomogeneously in the area at risk (uptake ratio was 1.89 ± 0.20). Then the uptake declined gradually over 1 month. OI5V uptake ratios at day 7, 14, and 1 month were 1.52 ± 0.17, 1.34 ± 0.13, and 1.16 ± 0.15, respectively. Uptake of OI5V was significantly blocked by piperazine dihydrochloride, that is known as selective Sig-1R agonist. Conclusions: Significant I-125 labeled OI5V uptake in the area at risk at day 3 was observed and the uptake decreased gradually over 1 month. These results indicate that imaging with OI5V is a promising tool for monitoring cardiac Sig-1R expression after myocardial severe ischemia and reperfusion.