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

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).

Structure-affinity-pharmacokinetics relationships of In-labeled PSMA-targeted ligands with different albumin binders.

Introduction: Prostate-specific membrane antigen (PSMA) is a promising target for treating metastatic castration-resistant prostate cancer. Our previous report presented In- or Ac-labeled PSMA-NAT-DA1 (PNT-DA1) as a PSMA-targeted ligand. To improve its therapeutic efficiency, PNT-DA1 contains 4-(p-iodophenyl)butyric acid (IPBA), which is known as an albumin binder (ALB) moiety.

Effect of Linker Entities on Pharmacokinetics of In-Labeled Prostate-Specific Membrane Antigen-Targeting Ligands with an Albumin Binder.

In the field of radiopharmaceutical development targeting cancer, an albumin binder (ALB) is commonly used to improve accumulation of radioligands in tumors because it has high binding affinity for albumin and extends the circulation time of radioligands. The further development of ALB-containing radioligands is also expected to regulate their pharmacokinetics. In this study, we newly designed and synthesized [In]In-PNT-DA1 derivatives, prostate-specific membrane antigen (PSMA)-targeting radioligands including a functional linker (d-glutamic acid or 4-(aminomethyl)benzoic acid), and evaluated the relationships among the structure, albumin-binding affinity, and pharmacokinetics.

Fundamental evaluation regarding the relationship between albumin-binding and tumor accumulation of PSMA-targeting radioligands.

Objective: The marked success of prostate-specific membrane antigen (PSMA)-targeting radioligands with albumin binder (ALB) is attributed to the improvement of blood retention and tumor accumulation. [In]In-PNT-DA1, our PSMA-targeting radioligand with ALB, also achieved improved tumor accumulation due to its prolonged blood retention. Although the advantage of ALBs is related to their reversible binding to albumin, the relationship between albumin-binding and tumor accumulation of PSMA-targeting radioligands remains unclear because of the lack of information about radioligands with stronger albumin-binding than ALBs.

Synthesis and evaluation of In-labeled tetrapeptide-based compounds as single-photon emission computed tomography imaging probes targeting granzyme B.

Granzyme B is an attractive target as a biomarker for contributing to improve the treatment with immune checkpoint inhibitor (ICI). In this study, we designed novel In-labeled granzyme B-targeting single-photon emission computed tomography (SPECT) imaging probes, [ In]IDT and [ In]IDAT. Nonradioactive In-labeled granzyme B-targeting compounds ([ In]IDT, [ In]IDAT) showed the affinity for recombinant mouse granzyme B.