As an element-equivalent theranostic pair, lead-203 (²⁰³Pb, 100% EC, half-life = 51.92 h) and lead-212 (²¹²Pb, 100% β^–, half-life = 10.64 h), through the emission of γ rays and an α particle in its decay chain, respectively, can aid in the development of personalized targeted radionuclide treatment for advanced and currently untreatable cancers. With these isotopes currently being used in clinical trials, an understanding of the relationship between the chelator structure, ability to incorporate the radiometal, and metal–complex stability is needed to help design appropriate chelators for clinical use. Herein, we report an investigation into the effect of ring size in macrocyclic chelators where pyridine, an intermediate Lewis base, acts as an electron donor toward lead. Crown-4Py (4,7,13,16-tetrakis(pyridin-2-ylmethyl)-1,10-dioxa-4,7,13,16-tetraazacyclooctadecane), cyclen-4Py (1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane), and NOON-2Py (7,16-bis(pyridin-2-ylmethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane) were synthesized and analyzed for their ability to coordinate Pb²⁺. Metal complex stability was investigated via [²⁰³Pb]Pb²⁺ radiolabeling studies, ¹H NMR spectroscopy, X-ray crystallography, and potentiometry. With the smallest macrocyclic backbone, cyclen-4Py had the highest radiochemical yield, while, in descending order, crown-4Py and NOON-2Py had the lowest. Thermodynamic stability constants (log K_ML) of 19.95(3), 13.29(5), and 11.67 for [Pb(Cyclen-4Py)]²⁺, [Pb(Crown-4Py)]²⁺, and [Pb(NOON-2Py)]²⁺, respectively, correlated with their radiochemical yields. The X-ray crystal structure of the least stable complexes [Pb(NOON-2Py)]²⁺ revealed a hemidirected Pb²⁺ center, as reflected by a void within the coordination sphere, and [Pb(Crown-4Py)]²⁺ showed an average Pb–N pyridine interatomic distance of >3 Å. By contrast, the crystal structure of [Pb(Cyclen-4Py)]²⁺ showed shorter Pb–N pyridine interactions, and in solution, only one highly symmetric isomer existed for this complex, whereas conformational flexibility was observed for both [Pb(Crown-4Py)]²⁺ and [Pb(NOON-2Py)]²⁺ at the NMR timescale. This study illustrates the importance of the macrocyclic backbone size when incorporating bulky electron-donor groups into the design of a macrocyclic chelator as it affects the accessibility of lead to the donor arms. Our results show that cyclen-4Py is a promising chelator for future studies with this theranostic pair.

中文翻译：

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评价大环尺寸对含吡啶基螯合剂中 [203Pb]Pb(II) 配合物稳定性的影响

作为元素等效的治疗诊断对，铅 203 ( ²⁰³ Pb, 100% EC, 半衰期 = 51.92 h) 和铅 212 ( ²¹² Pb, 100% β ^–, 半衰期 = 10.64 h)，分别通过在其衰变链中发射 γ 射线和 α 粒子，可以帮助开发针对晚期和目前无法治愈的癌症的个性化靶向放射性核素治疗。由于这些同位素目前用于临床试验，因此需要了解螯合剂结构、结合放射性金属的能力和金属复合物稳定性之间的关系，以帮助设计适合临床使用的螯合剂。在此，我们报告了对大环螯合剂中环大小影响的研究，其中吡啶（一种中间路易斯碱）作为铅的电子供体。Crown-4Py (4,7,13,16-tetrakis(pyridin-2-ylmethyl)-1,10-dioxa-4,7,13,16-tetraazacyclooctadecane), cyclen-4Py (1,4,7,10- tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane) 和 NOON-2Py (7,²⁺。通过[ ²⁰³ Pb]Pb ²⁺放射性标记研究、¹ H NMR 光谱、X 射线晶体学和电位测定法研究金属配合物的稳定性。在大环骨架最小的情况下，cyclen-4Py的放化学产率最高，而从高到低，crown-4Py和NOON-2Py最低。[Pb( Cyclen - 4Py )] ²⁺、[Pb(Crown-4Py)] ₂₊^和[Pb(NOON- 2Py)] ²⁺分别与它们的放射化学产率相关。^{最不稳定配合物 [Pb(NOON-2Py)] 2+}的 X 射线晶体结构揭示了一个半定向的 Pb²⁺中心，如配位球内的空隙所反映的那样，[Pb(Crown-4Py)] ²⁺显示平均 Pb-N 吡啶原子间距离 > 3 Å。相比之下，[Pb(Cyclen-4Py)] ²⁺的晶体结构表现出较短的 Pb-N 吡啶相互作用，在溶液中，该复合物仅存在一种高度对称的异构体，而 [Pb(Crown -4Py)] ²⁺和 [Pb(NOON-2Py)] ²⁺在核磁共振时间尺度。这项研究说明了大环骨架尺寸在将大电子供体基团纳入大环螯合剂设计时的重要性，因为它会影响铅对供体臂的可及性。我们的研究结果表明，cyclen-4Py 是一种很有前途的螯合剂，可用于未来使用这种治疗诊断对进行的研究。