Ding_2022_Mol.Pharm_19_3429

Fibroblast activation protein inhibitor (FAPI) is a novel quinoline-based radiopharmaceutical that has theranostic potential, yet the limited tumor retention hinders late-time diagnosis and radionuclide treatment. This study synthesized four albumin-binding FAPIs (TE-FAPI-01 to 04) and evaluated their in vitro stability, binding affinity, in vivo biodistribution, and tumor uptake with (68)Ga, (86)Y, and (177)Lu labeling, aiming to select the best molecule that has favorable pharmacokinetics to extend the blood circulation and tumor uptake in FAP-expressing tumors. All TE-FAPIs were stable in saline and plasma and displayed high FAP-binding affinity, with IC(50) values ranging from 3.96 to 34.9 nmol/L. The capabilities of TE-FAPIs to be retained in circulation were higher than that of FAPI-04, and TE-FAPI-04 displayed minimum physiological uptake in major organs compared with other molecules. TE-FAPI-03 and TE-FAPI-04 exhibited persistent tumor accumulation, with tumor radioactivity 24 h after administration of 2.84 +/- 1.19%ID/g and 3.86 +/- 1.15%ID/g for (177)Lu-TE-FAPI-03 and (177)Lu-TE-FAPI-04, respectively, both of which outperformed (177)Lu-FAPI-04 (0.34 +/- 0.07%ID/g). TE-FAPI-04 was recognized as the albumin-binding FAPI with the most favorable pharmacokinetics and imaging performance. The enhanced circulation half-life and tumor uptake of TE-FAPI-04 aided the theranostics of malignant tumors and warrant further clinical investigations.