Novel Radiotheranostic Ligands Targeting Prostate-Specific Membrane Antigen Based on Dual Linker Approach

Nobuki Kazuta; Kazuma Nakashima; Yuta Tarumizu; Takumi Sato; Yoshifumi Maya; Hiroyuki Watanabe; Masahiro Ono

doi:10.1021/acs.molpharmaceut.4c00974

Novel Radiotheranostic Ligands Targeting Prostate-Specific Membrane Antigen Based on Dual Linker Approach

Mol Pharm. 2024 Nov 30. doi: 10.1021/acs.molpharmaceut.4c00974. Online ahead of print.

Authors

Nobuki Kazuta¹, Kazuma Nakashima¹, Yuta Tarumizu², Takumi Sato², Yoshifumi Maya², Hiroyuki Watanabe¹, Masahiro Ono¹

Affiliations

¹ Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
² Research Center, Nihon Medi-Physics Co., Ltd., 3-1 Kitasode, Sodegaura-shi, Chiba 299-0266, Japan.

PMID: 39614820
DOI: 10.1021/acs.molpharmaceut.4c00974

Abstract

Radiotheranostics using prostate-specific membrane antigen (PSMA)-targeting radioligands offers precision medicine by performing radionuclide therapy based on results of diagnosis. Albumin binder (ALB) binds to albumin reversibly and contributes to effective radiotheranostics by enhancing tumor accumulation of PSMA-targeting radioligands. We newly developed two ALB-containing PSMA-targeting radioligands including dual functional linkers, a hydrophilic linker, d-glutamic acid, and a hydrophobic linker, 4-(aminomethyl)benzoic acid, with the opposite arrangement (PNT-DA6 and PNT-DA7). A biodistribution study of [¹¹¹In]In-PNT-DA6 indicated that the introduction and arrangement of dual functional linkers contributed to improved pharmacokinetics. A single photon emission computed tomography study of [¹¹¹In]In-PNT-DA6 produced a clear PSMA-expressing tumor image. Moreover, [²²⁵Ac]Ac-PNT-DA6 showed the inhibition of tumor growth in targeted radionuclide therapy in PSMA-expressing tumor-bearing mice. These results indicated that [¹¹¹In]In-PNT-DA6 and [²²⁵Ac]Ac-PNT-DA6 exhibited useful characteristics as PSMA-targeting radiotheranostic ligands.

Keywords: 4-(aminomethyl)benzoic acid; albumin binder; d-glutamic acid; dual functional linkers; prostate-specific membrane antigen; radiotheranostics.