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

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.