Novel Generation of FAP Inhibitor-Based Homodimers for Improved Application in Radiotheranostics.

Radiopharmaceuticals based on the highly potent FAP inhibitor (FAPi) UAMC-1110 have shown great potential in molecular imaging, but the short tumor retention time of the monomers do not match the physical half-lives of the important therapeutic radionuclides Lu and Ac. This was improved with the dimer DOTAGA.(SA.FAPi), but pharmacological and radiolabeling properties still need optimization. Therefore, the novel FAPi homodimers DO3A.Glu.(FAPi) and DOTAGA.Glu.(FAPi). were synthesized and quantitatively radiolabeled with Ga, Y, Lu and Ac. The radiolabeled complexes showed high hydrophilicity and were generally stable in human serum (HS) and phosphate-buffered saline (PBS) at 37 °C over two half-lives, except for [Ac]Ac-DOTAGA.Glu.(FAPi) in PBS. In vitro affinity studies resulted in subnanomolar IC values for FAP and high selectivity for FAP over the related proteases PREP and DPP4 for both compounds as well as for [Lu]Lu-DOTAGA.Glu.(FAPi). In a first proof-of-principle patient study (medullary thyroid cancer), [Lu]Lu-DOTAGA.Glu.(FAPi) was compared to [Lu]Lu-DOTAGA.(SA.FAPi). High uptake and long tumor retention was observed in both cases, but [Lu]Lu-DOTAGA.Glu.(FAPi) significantly reduces uptake in non-target and critical organs (liver, colon). Overall, the novel FAPi homodimer DOTAGA.Glu.(FAPi) showed improved radiolabeling in vitro and pharmacological properties in vivo compared to DOTAGA.(SA.FAPi). [Lu]Lu-DOTAGA.Glu.(FAPi) and [Ac]Ac-DOTAGA.Glu.(FAPi) appear promising for translational application in patients.