Development of highly-sensitive evaluation method of endothelial cell function and early diagnostic procedure of atherosclerosis by positron emission tomography

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Early detection of atherosclerosis complicated with hypertension, diabetes mellitus or hyperlipidemia is clinically very crucial. Diagnostic procedure of atherosclerosis so far have many problems; for example, they are very insensitive and detect only advanced lesions or they are very invasive and require high technique. This research project aims at establishment of a new diagnostic method of atherosclerosis to evaluate the decreased activity of nitric oxide (NO) synthase (NOS) in endothelial cells by utilizing PET.We obtained the following results:1. We succeeded in the labeling of L-NAME, the NOS inhibitor by ィイD13ィエD1H and ィイD111ィエD1C.2. Using ィイD13ィエD1H-L-NAME, we demonstrated that uptake of L-NAME by endothelial cells can reflect the activity of NO production (NOS activity) in vitro.3. Using ィイD111ィエD1C-L-NAME, we succeeded in in vitro PET imaging of endothelial cells.4. Ionomycin, the calcium ionohore augmented the uptake of ィイD111ィエD1C-L-NAME and we could detect more intense imaging of endothelial cells treated with ionomycin compared with the control.These results suggest that PET imaging using labeled L-NAME can be the evaluation method of endothelial function (NO production). Towards the in vivo application of our method, search for metabolically more stable L-NAME-related compounds and their labeling for PET imaging are required.