Decadentate Acyclic Chelators for Lanthanum Radiopharmaceuticals

Two decadentate acyclic chelators bearing four picolinic acid groups appended on either an ethylenediamine (H4TPAEN) or a trans-1,2-cyclohexyldiamine (H4TPADAC) unit were explored as candidates for lanthanum-based radiopharmaceutical development. The two chelators form ten-coordinated complexes with La3+ in the solid state, as evidenced by the corresponding X-ray structures and solution NMR studies. The La3+ complexes of TPAEN4– and TPADAC4– are characterized by high thermodynamic stability constants of log KLaL = 19.16(8) and 19.55(1), respectively. Kinetics studies indicate that the complexes dissociate following the acid-catalyzed and Cu2+-assisted pathways. Quantitative radiolabeling of both chelators with [135La]La3+ was achieved at pH ∼ 4–5 using straightforward protocols and low concentrations of the chelator (3 μM). Both in vitro and in vivo studies indicate that the [135La]La3+ complex of TPAEN4– is significantly more stable than the TPADAC4– analogue, with the former remaining intact and stable even after 60 min in vivo when injected to healthy mice.本研究探索了两款十齿无环螯合剂，其骨架分别为乙二胺（ethylenediamine）与反式-1,2-环己二胺（trans-1,2-cyclohexyldiamine），且均连有四个吡啶甲酸（picolinic acid）基团，对应配体分别记作H₄TPAEN与H₄TPADAC，作为镧基放射性药物开发的候选配体。固态条件下，两款螯合剂均可与La³⁺形成十配位配合物，相关结论通过对应X射线晶体结构（X-ray structures）与溶液核磁共振（solution NMR）研究得到验证。TPAEN⁴⁻与TPADAC⁴⁻对应的La³⁺配合物均具有较高的热力学稳定性，其稳定常数的对数形式分别为log K_{LaL}=19.16(8)与19.55(1)。动力学研究表明，该类配合物可通过酸催化与铜离子（Cu²⁺）辅助两条路径发生解离。采用简便的实验方案，在pH≈4~5、螯合剂浓度仅为3 μM的条件下，两款配体均可与[¹³⁵La]La³⁺实现定量放射性标记。体外（in vitro）与体内（in vivo）实验结果均显示，TPAEN⁴⁻对应的[¹³⁵La]La³⁺配合物的稳定性显著优于TPADAC⁴⁻的对应配合物：前者在注射至健康小鼠体内后，即使经过60分钟仍保持完整稳定的结构。