High Affinity and FAP-Targeted Radiotracers: A Potential Design Strategy to Improve the Pharmacokinetics and Tumor Uptake for FAP Inhibitors.

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts, making it an attractive target for both imaging and therapy of malignancy. This study presents a range of novel FAP inhibitors derived from amino derivatives of UAMC1110, incorporating polyethylene glycol and bulky groups containing bifunctional DOTA chelators. The compounds labeled with gallium-68 were developed and characterized to study biodistribution properties and tumor-targeting performance in nude mice bearing U87MG tumor xenografts. Several tracers of interest were screened due to the advantages in imaging and tumor-specific uptake. Positron emission tomography scans revealed that polyethylene glycol-modified 68Ga-3-3 had a rapid penetration within the neoplastic tissue and excellent tumor-to-background contrast. In a comparative biodistribution study, naphthalene-modified 68Ga-6-3 exhibited more significant tumor uptake (∼50% ID/g, 1 h p.i.) than 68Ga-3-3 and 10-fold higher than 68Ga-FAPI-04 under the same conditions. Remarkably, 68Ga-8-1, combining the two structural design strategies, obtains superior imaging performance.