Linker Manipulation with Beta ³ ‐Amino Acids Potentiates the Efficacy and Safety of PSMA Radiopharmaceuticals

ABSTRACT [ 177 Lu]Lu‐PSMA‐617 has achieved remarkable efficacy in the targeted radionuclide therapy (TRT) of metastatic castration‐resistant prostate cancer (mCRPC), yet challenges like salivary gland and renal toxicity remain. Linker manipulation is a well‐established strategy to enhance the efficacy and safety of prostate‐specific membrane antigen (PSMA)‐targeting radioligands. Notably, beta (β)‐amino acid moieties could improve in vivo pharmacological and pharmacokinetic profiles through modulating conformation, dynamics, and proteolytic susceptibility. Nevertheless, limited exploration of such moieties in PSMA‐targeting radioligands has been reported. Therefore, this study first developed a series of novel PSMA‐targeting radioligands through linker manipulation with beta 3 (β 3 )‐amino acids, aiming to potentiate the efficacy and safety. Preclinical evaluations showed that [ 68 Ga]Ga‐PSMA‐HK4 outperformed [ 68 Ga]Ga‐PSMA‐617 in tumor uptake, likely attributable to its optimized hydrophilicity and conformational flexibility. In a first‐in‐human trial involving 15 patients, [ 68 Ga]Ga‐PSMA‐HK4 demonstrated reduced salivary gland uptake (reductions of 35.8% and 48.1%) compared to [ 18 F]PSMA‐1007. It also exhibited superior diagnostic accuracy for equivocal lesions. Notably, the tumor uptake of [ 68 Ga]Ga‐PSMA‐HK4 in patients is overall higher than that of [ 68 Ga]Ga‐PSMA‐617. These findings underscore β 3 ‐amino acid linker manipulation with β 3 ‐amino acids as an effective strategy to enhance the performance of PSMA‐targeting radiopharmaceuticals, paving a new avenue for developing next‐generation agents and improving the precision of PSMA‐targeting TRT.