Synthesis, Evaluation, and First-in-Human Study of a Novel PSMA Radioligand Bearing Beta³‑Amino Acid Linkage

[18F]PSMA-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 [18F]PSMA-1007 by incorporating β3-amino acid linker and a DOTA chelator, yielding PSMA-HK9. Preclinical evaluations showed that [68Ga]Ga-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 [18F]PSMA-1007. A first-in-human study further characterized the in vivo pharmacokinetics of [68Ga]Ga-PSMA-HK9, revealing a trend toward higher tumor uptake compared with [68Ga]Ga-PSMA-617. Therapeutically, [177Lu]Lu-PSMA-HK9 demonstrated efficient cellular internalization and superior tumor inhibition compared with [177Lu]Lu-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.