Clinical translation of a novel FAPI dimer [⁶⁸Ga]Ga-LNC1013

Fibroblast activation protein (FAP) has emerged as a highly promising target for cancer diagnostic imaging and targeted radionuclide therapy. To exploit the therapeutic potential of suitably radiolabeled FAP inhibitors (FAPIs), this study presents the design and synthesis of a series of FAPI dimers to increase tumor uptake and retention. Preclinical evaluation and a pilot clinical PET imaging study were conducted to screen the lead compound with the potential for radionuclide therapy.

Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [⁶⁸Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer.

The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [⁶⁸Ga]Ga-LNC1013 had persistent tumor retention for at least 4 h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [⁶⁸Ga]Ga-LNC1013 was 8.24E-03 mSv/MBq. The human biodistribution of [⁶⁸Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [⁶⁸Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming ¹⁸F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [⁶⁸Ga]Ga-FAPI-46 decreased over time, whereas [⁶⁸Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4 h post-injection.

Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [⁶⁸Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [⁶⁸Ga]Ga-FAPI-46 and ¹⁸F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.