Synthesis of MC1 for Toxicology Study, Preceding Evaluation of [11C]MC1 as a PET Radioligandfor Imaging Neuroinflammation in Humans

Science Center, Bent Corridor

Cyclooxygenases COX-1 and COX-2 are enzymes responsible for the production of pro-inflammatory prostaglandins from arachidonic acid. Both enzymes are naturally found in animal kidneys, reproductive organs, and brain tissue; however, COX-2 is found sparingly in healthy bodies, only becoming significantly overexpressed in response to inflammatory illnesses (e.g. neurodegenerative diseases, cancer). Exploiting this inducement by developing a PET radioligand that is highly selective for COX-2 in the human brain could advance research regarding neuroinflammation. [11C]MC1 is a potential COX-2 radioligand planned for evaluation in PET imaging for the detection of neuroinflammation in humans. This project involved synthesis of MC1 for use in toxicology studies before testing the blocking ability of the radioligand [11C]MC1 on COX-2 in PET studies of neuroinflammation. MC1 synthesis followed a seven-step process modified from a published pathway. The compound was purified by preparatory HPLC after each of the final three steps. The final product was analyzed for purity with analytical HPLC and for chemical composition with 1H and 13C NMR spectroscopy. Both forms of NMR spectra for the final product match the predicted analyses for MC1 structure with a final yield of 104 mg (2.1% yield over synthetic pathway) at 98.24% purity. The sample will be sent to an external lab for toxicological testing, and MC1 will continue to be tested for viability as a blocker for use in PET neuroinflammation studies. Additional methodology will be applied to the pathway in an attempt to increase overall yield.