Rearmed Bifunctional Chelating Ligand for ²²⁵Ac/¹⁵⁵Tb Precision-Guided Theranostic Radiopharmaceuticals─H₄noneunpaX

Superior bifunctional chelating ligands, which can sequester both α-emitting radionuclides (²²⁵Ac, ²¹³Bi) and their diagnostic companions (¹⁵⁵Tb, ¹¹¹In), remain a formidable challenge to translating targeted alpha therapy, with complementary diagnostic imaging, to the clinic. H₄noneupaX, a chelating ligand with an unusual diametrically opposed arrangement of pendant donor groups, has been developed to this end. H₄noneunpaX preferentially complexes Ln³⁺ and An³⁺ ions, forming thermodynamically stable (pLa = 17.8, pLu = 21.3) and kinetically inert complexes─single isomeric species by nuclear magnetic resonance and density functional theory. Metal binding versatility demonstrated in radiolabeling [¹¹¹In]In³⁺, [¹⁵⁵Tb]Tb³⁺, [¹⁷⁷Lu]Lu³⁺, and [²²⁵Ac]Ac³⁺ achieved high molar activities under mild conditions. Efficient, scalable synthesis enabled in vivo evaluation of bifunctional H₄noneunpaX conjugated to two octreotate peptides targeting neuroendocrine tumors. Single photon emission computed tomography/CT and biodistribution studies of ¹⁵⁵Tb-radiotracers in AR42J tumor-bearing mice showed excellent image contrast, good tumor uptake, and high in vivo stability. H₄noneunpaX shows significant potential for theranostic applications involving ²²⁵Ac/¹⁵⁵Tb or ¹⁷⁷Lu/¹⁵⁵Tb.