Young Jennifer D, Abbate Vincenzo, Imberti Cinzia, Meszaros Levente K, Ma Michelle T, Terry Samantha Y A, Hider Robert C, Mullen Greg E, Blower Philip J
Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom; and.
Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
J Nucl Med. 2017 Aug;58(8):1270-1277. doi: 10.2967/jnumed.117.191882. Epub 2017 Apr 13.
The clinical impact and accessibility of Ga tracers for the prostate-specific membrane antigen (PSMA) and other targets would be greatly enhanced by the availability of a simple, 1-step kit-based labeling process. Radiopharmacy staff are accustomed to such procedures in the daily preparation of Tc radiopharmaceuticals. Currently, chelating agents used in Ga radiopharmaceuticals do not meet this ideal. The aim of this study was to develop and evaluate preclinically a Ga radiotracer for imaging PSMA expression that could be radiolabeled simply by addition of Ga generator eluate to a cold kit. A conjugate of a tris(hydroxypyridinone) (THP) chelator with the established urea-based PSMA inhibitor was synthesized and radiolabeled with Ga by adding generator eluate directly to a vial containing the cold precursors THP-PSMA and sodium bicarbonate, with no further manipulation. It was analyzed after 5 min by instant thin-layer chromatography and high-performance liquid chromatography. The product was subjected to in vitro studies to determine PSMA affinity using PSMA-expressing DU145-PSMA cells, with their nonexpressing analog DU145 as a control. In vivo PET imaging and ex vivo biodistribution studies were performed in mice bearing xenografts of the same cell lines, comparing Ga-THP-PSMA with Ga-HBED-CC-PSMA. Radiolabeling was complete (>95%) within 5 min at room temperature, showing a single radioactive species by high-performance liquid chromatography that was stable in human serum for more than 6 h and showed specific binding to PSMA-expressing cells (concentration giving 50% inhibition of 361 ± 60 nM). In vivo PET imaging showed specific uptake in PSMA-expressing tumors, reaching 5.6 ± 1.2 percentage injected dose per cubic centimeter at 40-60 min and rapid clearance from blood to kidney and bladder. The tumor uptake, biodistribution, and pharmacokinetics were not significantly different from those of Ga-HBED-CC-PSMA except for reduced uptake in the spleen. Ga-THP-PSMA has equivalent imaging properties but greatly simplified radiolabeling compared with other Ga-PSMA conjugates. THP offers the prospect of rapid, simple, 1-step, room-temperature syringe-and-vial radiolabeling of Ga radiopharmaceuticals.
一种基于试剂盒的简单一步标记法若能实现，将极大地提高用于前列腺特异性膜抗原（PSMA）及其他靶点的镓示踪剂的临床应用价值和可及性。放射性药物工作人员在日常制备锝放射性药物时已习惯此类操作流程。目前，镓放射性药物中使用的螯合剂并不符合这一理想要求。本研究的目的是在临床前开发并评估一种用于成像PSMA表达的镓放射性示踪剂，该示踪剂可通过向冷试剂盒中添加镓发生器洗脱液进行简单的放射性标记。合成了一种三（羟基吡啶酮）（THP）螯合剂与既定的基于尿素的PSMA抑制剂的共轭物，并通过将发生器洗脱液直接加入含有冷前体THP - PSMA和碳酸氢钠的小瓶中进行镓的放射性标记，无需进一步操作。5分钟后通过即时薄层色谱法和高效液相色谱法进行分析。使用表达PSMA的DU145 - PSMA细胞及其不表达PSMA的类似物DU145作为对照，对产物进行体外研究以确定PSMA亲和力。在携带相同细胞系异种移植瘤的小鼠中进行体内PET成像和离体生物分布研究，将Ga - THP - PSMA与Ga - HBED - CC - PSMA进行比较。在室温下5分钟内放射性标记完成（>95%），高效液相色谱显示单一放射性物质，该物质在人血清中稳定超过6小时，并显示出与表达PSMA的细胞特异性结合（产生50%抑制的浓度为361±60 nM）。体内PET成像显示在表达PSMA的肿瘤中有特异性摄取，在40 - 60分钟时达到每立方厘米5.6±1.2%注射剂量，并从血液快速清除至肾脏和膀胱。除脾脏摄取减少外，肿瘤摄取、生物分布和药代动力学与Ga - HBED - CC - PSMA无显著差异。与其他Ga - PSMA共轭物相比，Ga - THP - PSMA具有同等的成像特性，但放射性标记大大简化。THP为镓放射性药物的快速、简单、一步、室温下注射器和小瓶放射性标记提供了前景。
