Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 13705-13730 |
| Number of pages | 26 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 66 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 12 2023 |
Funding
We thank the TR13 Operations Group, consisting of Toni Epp, Ryley Morgan, and Spencer Staiger and led by David Prevost, for irradiations of Ca and Ba targets. We are grateful to Maryam Osooly and Dr. Sathiya Sekar for their assistance in performing SPECT/CT and biodistribution studies at the Centre for Comparative Medicine (CCM). We gratefully acknowledge the Natural Sciences and Engineering Research Council (NSERC) of Canada for a CREATE IsoSiM at TRIUMF research stipend (L.W.). We acknowledge both NSERC and the Canadian Institutes of Health Research (CIHR) for financial support via a Collaborative Health Research Project (CHRP to P.S., F.B., C.O.) and NSERC Discovery (H.Y., V.R., P.S., C.O.). TRIUMF receives federal funding via a contribution agreement with the National Research Council of Canada. We thank WestGrid and Compute Canada for access to their computational resources and Canada Foundation for Innovation (project no. 24513) for its support of the imaging facility ( http://invivoimaging.ca ). C.O. dedicates this paper to the memory of John Hugh McNeill CM PhD FRSC (1938-2023) supportive mentor, brilliant collaborator, and dear friend. We thank the TR13 Operations Group, consisting of Toni Epp, Ryley Morgan, and Spencer Staiger and led by David Prevost, for irradiations of Ca and Ba targets. We are grateful to Maryam Osooly and Dr. Sathiya Sekar for their assistance in performing SPECT/CT and biodistribution studies at the Centre for Comparative Medicine (CCM). We gratefully acknowledge the Natural Sciences and Engineering Research Council (NSERC) of Canada for a CREATE IsoSiM at TRIUMF research stipend (L.W.). We acknowledge both NSERC and the Canadian Institutes of Health Research (CIHR) for financial support via a Collaborative Health Research Project (CHRP to P.S., F.B., C.O.) and NSERC Discovery (H.Y., V.R., P.S., C.O.). TRIUMF receives federal funding via a contribution agreement with the National Research Council of Canada. We thank WestGrid and Compute Canada for access to their computational resources and Canada Foundation for Innovation (project no. 24513) for its support of the imaging facility (http://invivoimaging.ca). C.O. dedicates this paper to the memory of John Hugh McNeill CM PhD FRSC (1938-2023) supportive mentor, brilliant collaborator, and dear friend.