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

Superior bifunctional chelating ligands, which can sequester both a-emitting radionuclides (Ac-225,Bi-213) and their diagnostic companions (Tb-155,In-111), remain a formidable challenge to translating targeted alpha therapy, with complementary diagnostic imaging, to the clinic. H(4)noneupaX, a chelating ligand with an unusual diametrically opposed arrangement of pendant donor groups, has been developed to this end. H(4)noneunpaX preferentially complexes Ln(3+) and An(3+) 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 [In-111]In3+, [Tb-155]Tb3+, [Lu-177]Lu3+, and [Ac-225]Ac3+ achieved high molar activities under mild conditions. Efficient, scalable synthesis enabled in vivo evaluation of bifunctional H(4)noneunpaX conjugated to two octreotate peptides targeting neuroendocrine tumors. Single photon emission computed tomography/CT and biodistribution studies of Tb-155-radiotracers in AR42J tumor-bearing mice showed excellent image contrast, good tumor uptake, and high in vivo stability. H(4)noneunpaX shows significant potential for theranostic applications involving Ac-225/Tb-155 or Lu-177/Tb-155.