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

• Published in: Journal of medicinal chemistry Vol. 66; no. 19; pp. 13705 - 13730
• Main Authors: Wharton, Luke, Yang, Hua, Jaraquemada-Peláez, María de Guadalupe, Merkens, Helen, Engudar, Gokce, Ingham, Aidan, Koniar, Helena, Radchenko, Valery, Kunz, Peter, Schaffer, Paul, Bénard, François, Orvig, Chris
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.10.2023; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; EQUILIBRIUM-CONSTANTS; COMPLEXES; RADIOMETALS; NUCLEAR-DATA SHEETS; IN-111; HOCTAPA; SOLVATION; LU-177
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01151

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.