Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 40 Prague 2, Czech Republic.
Research Group Molecular Biology of Systemic Radiotherapy, German Cancer Research Center, Im Neuenheimer Feld 223, 69120 Heidelberg, Germany.
Dalton Trans. 2022 Jun 21;51(24):9541-9555. doi: 10.1039/d2dt01172g.
Ligands combining a bis(phosphonate) group with a macrocycle function as metal isotope carriers for radionuclide-based imaging and for treating bone metastases associated with several cancers. However, bis(phosphonate) pendant arms often slow down complex formation and decrease radiochemical yields. Nevertheless, their negative effect on complexation rates may be mitigated by using a suitable spacer between bis(phosphonate) and the macrocycle. To demonstrate the potential of bis(phosphonate) bearing macrocyclic ligands as a copper radioisotope carrier, we report the synthesis of a new cyclam derivative bearing a phosphinate-bis(phosphonate) pendant (Hte1P). The ligand showed a high selectivity to Cu over Zn and Ni ions, and the bis(phosphonate) group was not coordinated in the Cu complex, strongly interacting with other metal ions in solution. The Cu complex formed quickly, in 1 s, at pH 5 and at a millimolar scale. The complexation rates significantly differed under a ligand or metal ion excess due to the formation of reaction intermediates differing in their metal-to-ligand ratio and protonation state, respectively. The Cu-te1P complex also showed a high resistance to acid-assisted hydrolysis ( 2.7 h; 1 M HClO, 25 °C) and was effectively adsorbed on the hydroxyapatite surface. Hte1P radiolabeling with [Cu]CuCl was fast and efficient, with specific activities of approximately 30 GBq Cu per 1 μmol of ligand (pH 5.5, room temperature, 30 min). In a pilot experiment, we further demonstrated the excellent suitability of [Cu]Cu-te1P for imaging active bone compartments by dedicated small animal PET/CT in healthy mice and subsequently in a rat femoral defect model, in direct comparison with [F]fluoride. Moreover, [Cu]Cu-te1P showed a higher uptake in critical bone defect regions. Therefore, our study highlights the potential of [Cu]Cu-te1P as a PET radiotracer for evaluating bone healing in preclinical and clinical settings with a diagnostic value similar to that of [F]fluoride, albeit with a longer half-life (12.7 h) than F (1.8 h), thereby enabling extended observation times.
配体将双（膦酸酯）基团与大环结合在一起，作为基于放射性核素的成像的金属同位素载体，以及用于治疗与多种癌症相关的骨转移。然而，双（膦酸酯）侧臂常常会减缓配合物的形成并降低放射化学产率。然而，通过在双（膦酸酯）和大环之间使用合适的间隔物，可以减轻其对配合物形成速率的负面影响。为了证明含双膦酸酯的大环配体作为铜放射性同位素载体的潜力，我们报告了一种新的含有膦酸盐-双（膦酸酯）侧臂的环脒衍生物（Hte1P）的合成。该配体对 Cu 表现出相对于 Zn 和 Ni 离子的高选择性，并且双（膦酸酯）基团在 Cu 配合物中没有配位，而是与溶液中的其他金属离子强烈相互作用。在 pH 值为 5 和毫摩尔级时，Cu 配合物在 1 秒内快速形成。由于反应中间体在其金属与配体的比例和质子化状态上有所不同，因此在配体或金属离子过量时，配合物形成速率会有显著差异。Cu-te1P 配合物还具有很高的耐酸辅助水解能力（在 1 M HClO4 下 25°C 时需要 2.7 小时），并且可以有效地吸附在羟基磷灰石表面上。[Cu]CuCl 对 Hte1P 的放射性标记快速且高效，每个配体的放射性比活度约为 30 GBq Cu（pH 5.5，室温，30 分钟）。在一项初步实验中，我们进一步通过专门的小动物 PET/CT 在健康小鼠中以及随后在大鼠股骨缺损模型中，直接与[F]氟化物进行比较，证明了[Cu]Cu-te1P 非常适合用于成像活跃的骨区室。此外，[Cu]Cu-te1P 在关键的骨缺损区域的摄取量更高。因此，我们的研究强调了[Cu]Cu-te1P 作为 PET 放射性示踪剂在临床前和临床环境中评估骨愈合的潜力，其诊断价值与[F]氟化物相似，尽管其半衰期（12.7 h）比 F（1.8 h）长，从而能够延长观察时间。
