Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer

Abstract A novel synthesis of the translocator protein (TSPO) ligand 7-chloro- N , N ,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4 H -pyridazino[4,5- b ]indole-1-acetamide (SSR180575, 3 ) was achieved in four steps from commercially available starting materials. Focused structure–activity relationship development about the pyridazinoindole ring at the N3 position led to the discovery of 7-chloro- N , N ,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4 H -pyridazino[4,5- b ]indole-1-acetamide ( 14 ), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 ( 18 F) yielded 7-chloro- N , N ,5-trimethyl-4-oxo-3(6-[ 18 F]fluoropyridin-2-yl)-3,5-dihydro-4 H -pyridazino[4,5- b ]indole-1-acetamide ([ 18 F]- 14 ) in high radiochemical yield and specific activity. In vivo studies of [ 18 F]- 14 revealed this agent as a promising probe for molecular imaging of glioma.