Department of Nuclear Medicine, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany.
Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Eur J Nucl Med Mol Imaging. 2019 May;46(5):1081-1091. doi: 10.1007/s00259-018-4220-z. Epub 2019 Jan 3.
The aims of this study were to develop a prostate-specific membrane antigen (PSMA) ligand for labelling with different radioisotopes of lead and to obtain an approximation of the dosimetry of a simulated Pb-based alpha therapy using its Pb imaging analogue.
Four novel Glu-urea-based ligands containing the chelators p-SCN-Bn-TCMC or DO3AM were synthesized. Affinity and PSMA-specific internalization were studied in C4-2 cells, and biodistribution in C4-2 tumour-bearing mice. The most promising compound, Pb-CA012, was transferred to clinical use. Two patients underwent planar scintigraphy scans at 0.4, 4, 18, 28 and 42 h after injection, together with urine and blood sampling. The time-activity curves of source organs were extrapolated from Pb to Pb and the calculated residence times of Pb were forwarded to its unstable daughter nuclides. QDOSE and OLINDA were used for dosimetry calculations.
In vitro, all ligands showed low nanomolar binding affinities for PSMA. CA09 and CA012 additionally showed specific ligand-induced internalization of 27.4 ± 2.4 and 15.6 ± 2.1 %ID/10 cells, respectively. The Pb-labelled PSMA ligands were stable in serum for 72 h. In vivo, CA012 showed higher specific uptake in tumours than in other organs, and particularly showed rapid kidney clearance from 5.1 ± 2.5%ID/g at 1 h after injection to 0.9 ± 0.1%ID/g at 24 h. In patients, the estimated effective dose from 250-300 MBq of diagnostic Pb-CA012 was 6-7 mSv. Assuming instant decay of daughter nuclides, the equivalent doses projected from a therapeutic activity of 100 MBq of Pb-CA012 were 0.6 Sv to the red marrow, 4.3 Sv to the salivary glands, 4.9 Sv to the kidneys, 0.7 Sv to the liver and 0.2 Sv to other organs; representative tumour lesions averaged 13.2 Sv (where RBE5 is relative biological effectiveness factor 5). Compared to clinical experience with Bi-PSMA-617 and Ac-PSMA-617, the projected maximum tolerable dose was about 150 MBq per cycle.
Pb-CA012 is a promising candidate for PSMA-targeted alpha therapy of prostate cancer. The dosimetry estimate for radiopharmaceuticals decaying with the release of unstable daughter nuclides has some inherent limitations, thus clinical translation should be done cautiously.
本研究旨在开发一种用于标记不同放射性同位素铅的前列腺特异性膜抗原（PSMA）配体，并通过其 Pb 成像类似物获得模拟 Pb 基α治疗的剂量估算。
合成了四种新型含有螯合剂 p-SCN-Bn-TCMC 或 DO3AM 的 Glu-urea 基配体。在 C4-2 细胞中研究了亲和力和 PSMA 特异性内化，并在 C4-2 荷瘤小鼠中进行了生物分布研究。最有前途的化合物 Pb-CA012 被转移到临床使用。两名患者在注射后 0.4、4、18、28 和 42 小时进行平面闪烁扫描，并进行尿液和血液取样。源器官的时间-活性曲线从 Pb 外推到 Pb，并将 Pb 的计算居留时间转发到其不稳定的子核。使用 QDOSE 和 OLINDA 进行剂量计算。
在体外，所有配体对 PSMA 均表现出低纳摩尔结合亲和力。CA09 和 CA012 还分别显示出 27.4 ± 2.4%ID/10 细胞和 15.6 ± 2.1%ID/10 细胞的特异性配体诱导内化。标记的 PSMA 配体在血清中 72 小时内稳定。在体内，CA012 在肿瘤中的特异性摄取高于其他器官，特别是在注射后 1 小时从 5.1 ± 2.5%ID/g 迅速清除至 24 小时的 0.9 ± 0.1%ID/g。在患者中，从 250-300MBq 的诊断性 Pb-CA012 中估计的有效剂量为 6-7mSv。假设子核即刻衰减，从 100MBq 的 Pb-CA012 的治疗活性中预测的等效剂量为骨髓 0.6Sv、唾液腺 4.3Sv、肾脏 4.9Sv、肝脏 0.7Sv 和其他器官 0.2Sv；代表性肿瘤病变平均为 13.2Sv（其中 RBE5 是相对生物有效性因子 5）。与 Bi-PSMA-617 和 Ac-PSMA-617 的临床经验相比，预测的最大耐受剂量约为每个周期 150MBq。
Pb-CA012 是一种有前途的用于前列腺癌 PSMA 靶向α治疗的候选药物。用于放射性药物的剂量估算具有一些固有的局限性，因此临床转化应谨慎进行。
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