Wang_2022_Front.Chem_10_939160

PURPOSE: (68)Ga-labeled fibroblast activation protein inhibitors, such as [(68)Ga]Ga-DOTA-FAPI-04 and [(68)Ga]Ga-DOTA-FAPI-46, have been successfully applied in positron emission tomography imaging of various tumor types. To broaden the PET tracers of different positron nuclides for imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of two (11)C-labeled FAP inhibitors, (11)C-RJ1101 and (11)C-RJ1102. METHODS: Two phenolic hydroxyl precursors based on a quinoline amide core coupled with a 2-cyanopyrrolidine moiety were coupled with [(11)C]CH(3)I to synthesize (11)C-RJ1101 and (11)C-RJ1102. In vivo small-animal PET and biological distribution studies of (11)C-RJ1101 and (11)C-RJ1102 compared to [(68)Ga]Ga-DOTA-FAPI-04 were conducted in nude mice bearing U87MG tumor xenografts at 30, 60, and 90min, respectively. RESULTS: (11)C-RJ1101 and (11)C-RJ1102 were synthesized in over 15% radiochemical yields, with specific activities of 67 GBq/micromol and 34 GBq/micromol, respectively, at the end of synthesis and radiochemical purities greater than 99%. In U87MG tumor xenograft PET studies, the three tracers experienced higher specific uptake at the tumor site. However, because of significant differences in metabolism and clearance, [(68)Ga]Ga-DOTA-FAPI-04 experienced high uptake in the kidney, whereas (11)C-RJ1101 and (11)C-RJ1102 showed high uptake in the liver and intestine. Biodistribution studies revealed significant hepatobiliary excretion of (11)C-RJ1101 and (11)C-RJ1102. 11C-RJ1102 showed higher specific tumor uptake in U87MG xenografts (1.71 +/- 0.08% injected dose per Gram of tissue [ID/g]) than (11)C-RJ1101 (1.34 +/- 0.10%ID/g) and [(68)Ga]Ga-DOTA-FAPI-04 (1.29 +/- 0.04%ID/g) after 30 min p. i. In orthotopic glioma models, the uptake values were 0.07 +/- 0.03% ([(68)Ga]Ga-DOTA-FAPI-04) and 0.16 +/- 0.03% ((11)C-RJ1102), respectively. CONCLUSION: (11)C-RJ1101 and (11)C-RJ1102 are interesting candidates for translation to the clinic, taking advantage of the shorter half-life and physical imaging properties of C-11.