Adapting the Picaga Platform for Sc18F/177Lu/68Ga Labeled FAP-Targeted Radiopharmaceuticals

Fibroblast activation protein (FAP)-targeted radiopharmaceuticals have emerged as promising pan-cancer imaging and therapy agents; however, currently available platforms do not support labeling with 18F, 68Ga, and 177Lu using a single molecular precursor. Here, we describe the development of a FAP-targeted, theranostic platform based on the picaga (mpatcn-derived) chelator, capable of coordinating 18F, 68Ga, and 177Lu, followed by targeted, in vivo delivery of the radioactive payload. We synthesized three picaga-FAPI conjugates incorporating alkyl, polyethylene-glycol and poly-glycine linker architectures and evaluated their radiolabeling efficiency, FAP binding affinity, radiochemical complex stability, and in vivo performance. In competitive binding assays, picaga-FAPI and picaga-PEG3-FAPI exhibited IC50 values of 23.5 and 36.3 nM, whereas picaga-(Gly)3-FAPI exhibited diminished binding affinity, preventing determination of a corresponding IC50 value. All conjugates were successfully radiolabeled with 18F, 68Ga, and 177Lu, although radiochemical performance and molar activity varied with linker architecture, ranging from 3.7−0.37 MBq/nmol. In a FAP-expressing HT1080 xenograft model, the picaga-FAPI conjugate consistently demonstrated the highest tumor uptake across all three radionuclides, with 6.91 ± 2.13, 7.23 ± 2.10, and 5.73 ± 2.96 % ID/g for 18F, 68Ga, and 177Lu respectively. Urine metabolite analysis confirmed that the 68Ga and 177Lu complexes remained >99% and 94% intact, respectively, whereas the Sc18F complex is excreted 41% intact. Radiolabeled picaga-FAPI exhibited both the highest molar activity and the highest tumor uptake, and blocking studies verified FAP-mediated accumulation. These results establish picaga-FAPI’s suitability as a single-precursor platform for the implementation of 18F, 68Ga, and 177Lu FAP-targeted radiopharmaceuticals.