posted on 2022-08-17, 15:20authored byJie Ding, Mengxin Xu, Junyi Chen, Pu Zhang, Li Huo, Ziren Kong, Zhibo Liu
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 68Ga, 86Y, and 177Lu 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
IC50 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 177Lu-TE-FAPI-03 and 177Lu-TE-FAPI-04,
respectively, both of which outperformed 177Lu-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.