Synthesis, Evaluation, and First-in-Human Study of a Novel PSMA Radioligand Bearing Beta ³ -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 <i>in vivo</i> 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.