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Linker manipulation is a well\u2010established strategy to enhance the efficacy and safety of prostate\u2010specific membrane antigen (PSMA)\u2010targeting radioligands. Notably, beta (\u03b2)\u2010amino 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\u2010targeting radioligands has been reported. Therefore, this study first developed a series of novel PSMA\u2010targeting radioligands through linker manipulation with beta\n                    <jats:sup>3<\/jats:sup>\n                    (\u03b2\n                    <jats:sup>3<\/jats:sup>\n                    )\u2010amino acids, aiming to potentiate the efficacy and safety. Preclinical evaluations showed that [\n                    <jats:sup>68<\/jats:sup>\n                    Ga]Ga\u2010PSMA\u2010HK4 outperformed [\n                    <jats:sup>68<\/jats:sup>\n                    Ga]Ga\u2010PSMA\u2010617 in tumor uptake, likely attributable to its optimized hydrophilicity and conformational flexibility. In a first\u2010in\u2010human trial involving 15 patients, [\n                    <jats:sup>68<\/jats:sup>\n                    Ga]Ga\u2010PSMA\u2010HK4 demonstrated reduced salivary gland uptake (reductions of 35.8% and 48.1%) compared to [\n                    <jats:sup>18<\/jats:sup>\n                    F]PSMA\u20101007. It also exhibited superior diagnostic accuracy for equivocal lesions. Notably, the tumor uptake of [\n                    <jats:sup>68<\/jats:sup>\n                    Ga]Ga\u2010PSMA\u2010HK4 in patients is overall higher than that of [\n                    <jats:sup>68<\/jats:sup>\n                    Ga]Ga\u2010PSMA\u2010617. These findings underscore \u03b2\n                    <jats:sup>3<\/jats:sup>\n                    \u2010amino acid linker manipulation with \u03b2\n                    <jats:sup>3<\/jats:sup>\n                    \u2010amino acids as an effective strategy to enhance the performance of PSMA\u2010targeting radiopharmaceuticals, paving a new avenue for developing next\u2010generation agents and improving the precision of PSMA\u2010targeting TRT.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202505128","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T05:02:42Z","timestamp":1768194162000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Linker Manipulation with Beta\n                    <sup>3<\/sup>\n                    \u2010Amino Acids Potentiates the Efficacy and Safety of PSMA Radiopharmaceuticals"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2299-4352","authenticated-orcid":false,"given":"Xin","family":"Gao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences &amp; 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