Effect of Structural Alteration in Albumin Binder Moiety on Tumor Accumulation of Somatostatin Receptor 2-Targeted Radioligands

Somatostatin receptor 2 (SSTR2) is a valuable target for the treatment of patients with neuroendocrine tumors (NETs). [¹⁷⁷Lu]-Lu-DOTA-TATE, an SSTR2-targeted ligand, is clinically used for therapy in patients with NETs; however, a low-absorbed dose in tumors remains a limitation. Albumin binders (ALBs) are commonly used to enhance the tumor accumulation of radioligands, but the effect of modulating ALB affinity has not been thoroughly investigated for DOTA-TATE-based SSTR2-targeted radioligands. In this study, we newly developed three DOTA-TATE-based radioligands with 4-(<i>p</i>-iodophenyl)-butyric acid ([¹¹¹In]-In-TATE-DA-I), 4-(<i>p</i>-bromophenyl)-butyric acid ([¹¹¹In]-In-TATE-DA-Br), and 4-(<i>p</i>-tolyl)-butyric acid ([¹¹¹In]-In-TATE-DA-CH₃) as ALB moieties. In the albumin-binding assay, the order of albumin-binding potency of each radioligand was consistent with that of the corresponding ALB moieties alone. In the biodistribution study, the radioligands with stronger albumin-binding potencies showed higher area under the curve (AUC) values in the blood. All ALB-containing radioligands exhibited higher tumor AUC values than [¹¹¹In]-In-DOTA-TATE, and the order of tumor AUC values corresponded with those of blood AUC values and albumin-binding potencies. Among them, [¹¹¹In]-In-TATE-DA-I showed the highest tumor AUC value and clearly visualized the SSTR2-positive tumor in SPECT/CT imaging. These findings highlight the importance of structural modification in the ALB moiety to enhance tumor accumulation of DOTA-TATE-based radioligands.