First-in-human evaluation of four novel PSMA-targeted PET radiotracers with non-canonical amino acid linkage: A comparative study.

PSMA-targeted radiopharmaceuticals have substantially advanced the management of prostate cancer; however, high nonspecific uptake in organs such as salivary glands and kidneys remains a clinical challenge. In our previous studies, incorporation of non-canonical amino acid linkers was shown to reduce off-target uptake while preserving or even enhancing tumor accumulation of PSMA-targeted radiotracers. Here, we present a first-in-human head-to-head comparison in which each of four linker-optimized PSMA radiotracers-[68Ga]Ga-PSMA-HK4, [68Ga]Ga-PSMA-HK7, [68Ga]Ga-PSMA-Y55, and [68Ga]Ga-PSMA-Y81-was individually compared with either [68Ga]Ga-PSMA-617 or [68Ga]Ga-PSMA-11, evaluating their in vivo pharmacokinetics and diagnostic performance in eight prostate cancer patients. Preclinical data demonstrated that all four radiotracers achieved comparable or enhanced tumor uptake, with [68Ga]Ga-PSMA-Y55 and [68Ga]Ga-PSMA-Y81 showing reduced renal accumulation relative to [68Ga]Ga-PSMA-617. Clinically, [68Ga]Ga-PSMA-HK4 and [68Ga]Ga-PSMA-HK7 exhibited lower salivary gland uptake, whereas [68Ga]Ga-PSMA-Y55 and [68Ga]Ga-PSMA-Y81 showed decreased renal retention compared with reference tracers. Tumor uptake of [68Ga]Ga-PSMA-HK4 and [68Ga]Ga-PSMA-Y55 was comparable to [68Ga]Ga-PSMA-617, while [68Ga]Ga-PSMA-HK7 and [68Ga]Ga-PSMA-Y81 displayed prolonged blood pool and cardiac retention. These clinical findings indicate that β3-amino acid linkers effectively reduced salivary gland uptake, while linker stereochemistry modulated renal clearance of PSMA radiotracers. Even subtle atomic-level linker variations resulted in substantial preclinical and clinical pharmacokinetic divergence, highlighting the necessity of precise molecular engineering in PSMA radiopharmaceuticals to achieve an improved tumor therapeutic index while reducing nonspecific toxicity.