Novel\nRadiotheranostic Ligands Targeting\nProstate-Specific Membrane Antigen\nBased on Dual Linker Approach

Radiotheranostics using prostate-specific\nmembrane antigen\n(PSMA)-targeting\nradioligands offers precision medicine by performing radionuclide\ntherapy based on results of diagnosis. Albumin binder (ALB) binds\nto albumin reversibly and contributes to effective radiotheranostics\nby enhancing tumor accumulation of PSMA-targeting radioligands. We\nnewly developed two ALB-containing PSMA-targeting radioligands including\ndual functional linkers, a hydrophilic linker, d-glutamic\nacid, and a hydrophobic linker, 4-(aminomethyl)benzoic acid, with\nthe opposite arrangement (PNT-DA6 and PNT-DA7). A biodistribution\nstudy of [<sup>111</sup>In]In-PNT-DA6 indicated that the introduction\nand arrangement of dual functional linkers contributed to improved\npharmacokinetics. A single photon emission computed tomography study\nof [<sup>111</sup>In]In-PNT-DA6 produced a clear PSMA-expressing tumor\nimage. Moreover, [<sup>225</sup>Ac]Ac-PNT-DA6 showed the inhibition\nof tumor growth in targeted radionuclide therapy in PSMA-expressing\ntumor-bearing mice. These results indicated that [<sup>111</sup>In]In-PNT-DA6\nand [<sup>225</sup>Ac]Ac-PNT-DA6 exhibited useful characteristics\nas PSMA-targeting radiotheranostic ligands.