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

The element-equivalent theranostic pair lead-203 (203Pb, 100% EC, t1/2 = 51.92 h) and lead-212 (212Pb, 100% β- to α emitting 212Bi, t1/2 = 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.