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.