Yamaguchi Keisei, Kazuta Nobuki, Tsuchihashi Shohei, Watanabe Hiroyuki, Ono Masahiro
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Nucl Med Biol. 2024 Nov-Dec;138-139:108945. doi: 10.1016/j.nucmedbio.2024.108945. Epub 2024 Aug 3.
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. However, few reports have examined the relationship between the chemical modification of the ALB moiety and pharmacokinetics of PSMA-targeted radioligands. To assess this relationship, we designed, synthesized, and evaluated four [In]In-PNT-DA1 analogues with ALB moieties different from IPBA.
The [In]In-PNT-DA1 analogues were synthesized from their corresponding precursors through ligand substitution reaction. The stability of [In]In-PNT-DA1 analogues in mouse plasma, their affinity for human serum albumin (HSA), their binding to mouse plasma proteins, and their affinity for PSMA were evaluated in vitro. The tissue distribution profile of the radioligands was assessed in biodistribution studies using LNCaP tumor-bearing nude mice.
All [In]In-PNT-DA1 analogues were obtained at a high radiochemical yield and purity. These analogues were highly stable in mouse plasma after 24 h. The binding affinity for HSA significantly varied among the different ALB moieties. Moreover, high affinity for mouse plasma proteins was observed for all [In]In-PNT-DA1 analogues compared with their counterparts without an ALB moiety. The affinity for PSMA was comparable for all radioligands. In the biodistribution assay, the pharmacokinetics of [In]In-PNT-DA1 analogues varied markedly depending on the type of ALB moiety. In particular, tumor area under the curve (AUC) values were increased for radioligands with higher blood retention, while some previous studies reported that compounds with moderate blood retention exhibited the highest tumor AUC values.
The introduction of an appropriate ALB moiety into the ligand may lead to the development of more useful PSMA-targeted radioligands with higher tumor accumulation.
前列腺特异性膜抗原（PSMA）是治疗转移性去势抵抗性前列腺癌的一个有前景的靶点。我们之前的报告提出了铟或锕标记的PSMA-NAT-DA1（PNT-DA1）作为一种靶向PSMA的配体。为了提高其治疗效率，PNT-DA1含有4-（对碘苯基）丁酸（IPBA），它是一种已知的白蛋白结合剂（ALB）部分。然而，很少有报告研究ALB部分的化学修饰与靶向PSMA的放射性配体的药代动力学之间的关系。为了评估这种关系，我们设计、合成并评估了四种与IPBA不同的ALB部分的[铟]铟-PNT-DA1类似物。
[铟]铟-PNT-DA1类似物通过配体取代反应从其相应的前体合成。在体外评估了[铟]铟-PNT-DA1类似物在小鼠血浆中的稳定性、它们与人血清白蛋白（HSA）的亲和力、它们与小鼠血浆蛋白的结合以及它们与PSMA的亲和力。使用携带LNCaP肿瘤的裸鼠在生物分布研究中评估放射性配体的组织分布情况。
所有[铟]铟-PNT-DA1类似物均以高放射化学产率和纯度获得。这些类似物在24小时后在小鼠血浆中高度稳定。不同ALB部分对HSA的结合亲和力有显著差异。此外，与没有ALB部分的对应物相比，所有[铟]铟-PNT-DA1类似物对小鼠血浆蛋白都表现出高亲和力。所有放射性配体对PSMA的亲和力相当。在生物分布测定中，[铟]铟-PNT-DA1类似物的药代动力学根据ALB部分的类型有显著差异。特别是，具有较高血液滞留率的放射性配体的肿瘤曲线下面积（AUC）值增加，而一些先前的研究报告称血液滞留率适中的化合物表现出最高的肿瘤AUC值。
在配体中引入合适的ALB部分可能会导致开发出更有用的、具有更高肿瘤蓄积的靶向PSMA的放射性配体。
