Bendre_2024_Eur.J.Med.Chem_268_116238

Fibroblast activation protein-alpha (FAP) is a marker of cancer-associated fibroblasts (CAFs) that constitute a significant portion of most carcinomas. Since it plays a critical role in tumor growth and metastasis, its timely detection to identify tumor lesions in early developmental stages using targeted radiopharmaceuticals has gained significant impetus. In the present work, two novel FAP-targeted precursors SB03178 and SB04033 comprising of an atypical benzo[h]quinoline construct were synthesized and either chelated to diagnostic radionuclide gallium-68 or therapeutic radionuclide lutetium-177, with <=90% radiochemical purities and 22-76% decay-corrected radiochemical yields. (nat)Ga-labeled complexes displayed dose-dependent FAP inhibition, with binding potency of (nat)Ga-SB03178 being -17 times higher than (nat)Ga-SB04033. To evaluate their pharmacokinetic profiles, PET imaging and ex vivo biodistribution analyses were executed in FAP-overexpressing HEK293T:hFAP tumor-bearing mice. While both tracers displayed clear tumor visualization that was primarily FAP-arbitrated, with negligible uptake in most peripheral tissues, [(68)Ga]Ga-SB03178 demonstrated higher tumor uptake and superior tumor-to-background contrast ratios than [(68)Ga]Ga-SB04033. (177)Lu-labeled SB03178 was subjected to tumor retention studies, mouse dosimetry profiling and mouse-to-human dose extrapolations also using the HEK293T:hFAP tumor model. [(177)Lu]Lu-SB03178 exhibited a combination of high and sustained tumor uptake, with excellent tumor-to-critical organ uptake ratios resulting in a high radiation absorbed dose to the tumor and a low estimated whole-body dose to humans. Our preliminary findings are considerably encouraging to support clinical development of [(68)Ga]Ga-/[(177)Lu]Lu-SB03178 theranostic pair for use in a vast majority of FAP-overexpressing neoplasms, particularly carcinomas.