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 ( 203 Pb, 100% EC, t 1/2 = 51.92 h) and lead-212 ( 212 Pb, 100% β – to α emitting 212 Bi, 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 N 1, N 7 ( N-trans )-symmetrical cyclen-based chelators─DO2A-2Py and DCMC-2Py─designed to form thermodynamically stable and kinetically inert Pb 2+ complexes. Protonation and stability constants determined by pH-dependent 1 H 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 Pb 2+ complexes with the expected trans arrangement. Quantitative radiolabeling of [ 203 Pb]Pb 2+ 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 Pb 2+ or EDTA, over 52 h, remaining >96% ([ 203 Pb]Pb 2+ -DO2A-2Py) and >94% ([ 203 Pb]Pb 2+ -DCMC-2Py) intact. Together, these findings reveal DO2A-2Py and DCMC-2Py as highly promising chelators for [ 203/212 Pb]Pb 2+ radiopharmaceuticals.