Carboxylic- and Amide Donor-Functionalized Pyridine- N - trans -Substituted Cyclen-Based Chelators for 203 Pb/ 212 Pb Theranostic Radiopharmaceuticals

The element-equivalent theranostic pair lead-203 (²⁰³Pb, 100% EC, t_1/2 = 51.92 h) and lead-212 (²¹²Pb, 100% β^- to α emitting ²¹²Bi, t_1/2 = 10.64 h) enable both diagnostic imaging and targeted therapy of disease within a single chemical framework through the emission of γ-rays and α-particles, respectively. In efforts to further advance the clinical potential of this theranostic pair, we report the synthesis and evaluation of two N¹,N⁷ (N-trans)-symmetrical cyclen-based chelators─DO2A-2Py and DCMC-2Py─designed to form thermodynamically stable and kinetically inert Pb²⁺ complexes. Protonation and stability constants determined by pH-dependent ¹H NMR titrations revealed that [Pb(DO2A-2Py)] and [Pb(DCMC-2Py)]²⁺ form complexes with high thermodynamic stability (logβ_{[Pb(DO2A-2Py)]} = 22.05 ± 0.05 and logβ_{[Pb(DCMC-2Py)]}²⁺ = 18.62 ± 0.05). Structural analysis by single crystal X-ray diffractometry revealed eight-coordinate Pb²⁺ complexes with the expected trans arrangement. Quantitative radiolabeling of [²⁰³Pb]Pb²⁺ was achieved for both DO2A-2Py and DCMC-2Py under mild, highly dilute reaction conditions (pH 7, 10 min reaction time). The resulting complexes exhibited remarkable kinetic inertness in serum, and in the presence of excess Pb²⁺ or EDTA, over 52 h, remaining >96% ([²⁰³Pb]Pb²⁺-DO2A-2Py) and >94% ([²⁰³Pb]Pb²⁺-DCMC-2Py) intact. Together, these findings reveal DO2A-2Py and DCMC-2Py as highly promising chelators for [^203/212Pb]Pb²⁺ radiopharmaceuticals.