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

Abstract

Superior bifunctional chelating ligands, which can sequester both α-emitting radionuclides ( 225 Ac, 213 Bi) and their diagnostic companions ( 155 Tb, 111 In), 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 [ 111 In]In 3+, [ 155 Tb]Tb 3+, [ 177 Lu]Lu 3+, and [ 225 Ac]Ac 3+ 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 155 Tb-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 225 Ac/ 155 Tb or 177 Lu/ 155 Tb.