The strategy of using radioligands for targeting the prostate-specific membrane antigen (PSMA) revealed to be promising for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently developed albumin-binding PSMA radioligands showed a remarkably increased tumor uptake because of the enhanced blood circulation, but higher accumulation of activity was also observed in off-target organs and tissues. The aim of this study was to investigate the option of using fast-cleared, small-molecular-weight PSMA inhibitors (PSMA-11, 2-PMPA, and ZJ-43) to reduce the kidney uptake of [¹⁷⁷Lu]Lu-PSMA-ALB-56, a previously developed albumin-binding PSMA radioligand. Dual-isotope SPECT/CT imaging was performed with tumor-bearing mice coinjected with [¹⁷⁷Lu]Lu-PSMA-ALB-56 and a 2.5-fold molar excess of [⁶⁷Ga]Ga-PSMA-11. At early timepoints after injection, the high renal uptake of [⁶⁷Ga]Ga-PSMA-11 reduced the accumulation of [¹⁷⁷Lu]Lu-PSMA-ALB-56 in the kidneys substantially, whereas the tumor uptake of [¹⁷⁷Lu]Lu-PSMA-ALB-56 was only slightly affected. These findings were confirmed in biodistribution studies, which revealed reduced uptake of [¹⁷⁷Lu]Lu-PSMA-ALB-56 in the kidneys due to coadministered unlabeled PSMA-11 (9.1 ± 0.8% IA/g vs 46 ± 11% IA/g; 1 h p.i.). The tumor uptake of [¹⁷⁷Lu]Lu-PSMA-ALB-56 was almost the same at 1 h p.i., irrespective of whether or not PSMA-11 was coinjected (24 ± 6% IA/g vs 27 ± 7% IA/g). The application of [¹⁷⁷Lu]Lu-PSMA-ALB-56 with 2-PMPA or ZJ-43, respectively, showed similar results in biodistribution studies. Among all three tested PSMA inhibitors, 2-PMPA, applied at a 2.5-fold molar excess relative to [¹⁷⁷Lu]Lu-PSMA-ALB-56, was most effective to improve the tumor-to-kidney ratios over the first hours after injection of [¹⁷⁷Lu]Lu-PSMA-ALB-56. The concept of using a PSMA inhibitor together with [¹⁷⁷Lu]Lu-PSMA-ALB-56 appears promising in view of a clinical translation of this and possibly other long-circulating PSMA radioligands.

中文翻译：

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白蛋白结合[177Lu] Lu-PSMA-ALB-56和快速清除的PSMA抑制剂的联合应用：药代动力学的优化。

使用放射配体靶向前列腺特异性膜抗原（PSMA）的策略显示出有望用于治疗转移性去势抵抗性前列腺癌（mCRPC）。最近开发的结合白蛋白的PSMA放射性配体由于血液循环的增强而显着增加了肿瘤的吸收，但是在脱靶器官和组织中也观察到了更高的活性积累。这项研究的目的是研究使用快速清除的小分子量PSMA抑制剂（PSMA-11、2-PMPA和ZJ-43）来减少[ ¹⁷⁷ Lu] Lu-PSMA肾脏摄取的选择。-ALB-56，先前开发的结合白蛋白的PSMA放射性配体。用荷瘤小鼠共注射[ ^177]进行双同位素SPECT / CT成像Lu] Lu-PSMA-ALB-56和[ ⁶⁷ Ga] Ga-PSMA-11摩尔过量2.5倍。在注射后的早期时间点，肾脏对[ ⁶⁷ Ga] Ga-PSMA-11的高摄入量显着降低了[ ¹⁷⁷ Lu] Lu-PSMA-ALB-56在肾脏中的积累，而对[ ¹⁷⁷ Lu] Lu的肿瘤吸收-PSMA-ALB-56仅受到轻微影响。这些发现在生物分布研究中得到了证实，该研究表明，由于共同使用未标记的PSMA-11，肾脏中[ ¹⁷⁷ Lu] Lu-PSMA-ALB-56的摄取减少（9.1±0.8％IA / g与46±11％IA / g ; pi 1小时）。[ ¹⁷⁷的肿瘤吸收无论是否注射PSMA-11，Lu-Lu-PSMA-ALB-56在注射后1 h几乎相同（24±6％IA / g对27±7％IA / g）。在生物分布研究中，分别使用2-PMPA或ZJ-43的[ ¹⁷⁷ Lu] Lu-PSMA-ALB-56的应用显示了相似的结果。在所有三种测试的PSMA抑制剂中，相对于[ ¹⁷⁷ Lu] Lu-PSMA-ALB-56摩尔过量2.5倍施用的2-PMPA最有效地改善了术后的肾脏与肾脏的比率注射[ ¹⁷⁷ Lu] Lu-PSMA-ALB-56。考虑到PSMA抑制剂和其他可能长循环的PSMA放射性配体的临床翻译，将PSMA抑制剂与[ ¹⁷⁷ Lu] Lu-PSMA-ALB-56一起使用的想法似乎很有希望。