Synthesis, Evaluation, and First-in-Human Study of a Novel PSMA Radioligand Bearing Beta 3 -Amino Acid Linkage

[ 18 F]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 beta 3 (β 3 )-amino acid effectively reduces salivary gland accumulation and enhances tumor uptake of PSMA-617. Here, we redesigned the scaffold of [ 18 F]PSMA-1007 by incorporating β 3 -amino acid linker and a DOTA chelator, yielding PSMA-HK9. Preclinical evaluations showed that [ 68 Ga]Ga-PSMA-HK9 demonstrated enhanced binding affinity, significantly reduced uptake in kidneys and salivary glands, and increased tumor uptake compared with the 68 Ga-labeled analog of [ 18 F]PSMA-1007. A first-in-human study further characterized the in vivo pharmacokinetics of [ 68 Ga]Ga-PSMA-HK9, revealing a trend toward higher tumor uptake compared with [ 68 Ga]Ga-PSMA-617. Therapeutically, [ 177 Lu]Lu-PSMA-HK9 demonstrated efficient cellular internalization and superior tumor inhibition compared with [ 177 Lu]Lu-PSMA-617, with acceptable safety profiles. These findings indicate the linker manipulation with β 3 -amino acid as an effective and promising strategy for optimizing the pharmacokinetics and pharmacodynamics performance of PSMA-targeted radioligands.