A Novel 68Ga‐Labeled 2‐Azabicyclo[3.1.0]Hexane‐3‐Carbonitrile‐Based Fibroblast Activation Protein‐Targeted Tracer for Cancer Imaging With Positron Emission Tomography

ABSTRACT Most of the reported small molecule‐based fibroblast activation protein (FAP)‐targeted radioligands are derived from UAMC1110 and contain a 4‐difluoro‐2‐cyanopyrrolidine moiety. In this study, we investigated the effect of replacing the 4‐difluoro‐2‐cyanopyrrolidine moiety of [68Ga]Ga‐FAPI‐04 with 2‐azabicyclo[3.1.0]hexane‐3‐carbonitrile on the in vitro/vivo FAP‐targeting capability. The newly derived 68Ga‐labeled FAP‐targeted tracer, [68Ga]Ga‐JC02076, was obtained in 43.5 ± 10.4% decay‐corrected radiochemical yield within 33.5 ± 5.8 min (n = 4). The radiochemical purity and molar activity were 97.2 ± 3.4% and 411.6 ± 232.5 GBq/μmol, respectively. Ga‐JC02076 showed good binding affinity for FAP (IC50 = 29.7 ± 3.5 nM). Most importantly, [68Ga]Ga‐JC02076 enabled clear visualization of HEK293T:hFAP tumor xenografts in PET images and had good tumor uptake (7.17 ± 2.19 %ID/g) and excellent tumor‐to‐bone (17.3 ± 6.99) and tumor‐to‐muscle (32.3 ± 12.5) uptake ratios at 1 h post‐injection. Our data suggest that N‐(4‐quinolinoyl)‐Gly‐(2‐azabicyclo[3.1.0]hexane‐3‐carbonitrile) is a promising pharmacophore for the design of FAP‐targeted tracers.