18FPSMA-1007 is widely used for prostate cancer imaging, but suffers from nonspecific accumulation in healthy tissues. Our previous work demonstrated that linker manipulation with beta3 (β3)-amino acid effectively reduces salivary gland accumulation and enhances tumor uptake of PSMA-617. Here, we redesigned the scaffold of 18FPSMA-1007 by incorporating β3-amino acid linker and a DOTA chelator, yielding PSMA-HK9. Preclinical evaluations showed that 68GaGa-PSMA-HK9 demonstrated enhanced binding affinity, significantly reduced uptake in kidneys and salivary glands, and increased tumor uptake compared with the 68Ga-labeled analog of 18FPSMA-1007. A first-in-human study further characterized the in vivo pharmacokinetics of 68GaGa-PSMA-HK9, revealing a trend toward higher tumor uptake compared with 68GaGa-PSMA-617. Therapeutically, 177LuLu-PSMA-HK9 demonstrated efficient cellular internalization and superior tumor inhibition compared with 177LuLu-PSMA-617, with acceptable safety profiles. These findings indicate the linker manipulation with β3-amino acid as an effective and promising strategy for optimizing the pharmacokinetics and pharmacodynamics performance of PSMA-targeted radioligands.
Gao et al. (Mon,) studied this question.