PMID- 27476138 OWN - NLM STAT- MEDLINE DCOM- 20170829 LR - 20171122 IS - 1464-3405 (Electronic) IS - 0960-894X (Linking) VI - 26 IP - 17 DP - 2016 Sep 1 TI - An efficient chelator for complexation of thorium-227. PG - 4318-21 LID - S0960-894X(16)30747-8 [pii] LID - 10.1016/j.bmcl.2016.07.034 [doi] AB - We present the synthesis and characterization of a highly efficient thorium chelator, derived from the octadentate hydroxypyridinone class of compounds. The chelator forms extremely stable complexes with fast formation rates in the presence of Th-227 (ambient temperature, 20min). In addition, mouse biodistribution data are provided which indicate rapid hepatobiliary excretion route of the chelator which, together with low bone uptake, supports the stability of the complex in vivo. The carboxylic acid group may be readily activated for conjugation through the varepsilon-amino groups of lysine residues in biomolecules such as antibodies. This chelator is a critical component of a new class of Targeted Thorium Conjugates (TTCs) currently under development in the field of oncology. CI - Copyright (c) 2016. Published by Elsevier Ltd. FAU - Ramdahl, Thomas AU - Ramdahl T AD - The Department of Thorium Research, Bayer AS, Drammensveien 288, 0283 Oslo, Norway. FAU - Bonge-Hansen, Hanne T AU - Bonge-Hansen HT AD - The Department of Thorium Research, Bayer AS, Drammensveien 288, 0283 Oslo, Norway. FAU - Ryan, Olav B AU - Ryan OB AD - The Department of Thorium Research, Bayer AS, Drammensveien 288, 0283 Oslo, Norway. FAU - Larsen, Smund AU - Larsen S AD - The Department of Thorium Research, Bayer AS, Drammensveien 288, 0283 Oslo, Norway. FAU - Herstad, Gunnar AU - Herstad G AD - Synthetica AS, Gaustadalleen 21, 0349 Oslo, Norway. FAU - Sandberg, Marcel AU - Sandberg M AD - Synthetica AS, Gaustadalleen 21, 0349 Oslo, Norway. FAU - Bjerke, Roger M AU - Bjerke RM AD - The Department of Thorium Research, Bayer AS, Drammensveien 288, 0283 Oslo, Norway. FAU - Grant, Derek AU - Grant D AD - The Department of Thorium Research, Bayer AS, Drammensveien 288, 0283 Oslo, Norway. FAU - Brevik, Ellen M AU - Brevik EM AD - The Department of Thorium Research, Bayer AS, Drammensveien 288, 0283 Oslo, Norway. FAU - Cuthbertson, Alan S AU - Cuthbertson AS AD - The Department of Thorium Research, Bayer AS, Drammensveien 288, 0283 Oslo, Norway. Electronic address: alan.cuthbertson@bayer.com. LA - eng PT - Journal Article DEP - 20160717 PL - England TA - Bioorg Med Chem Lett JT - Bioorganic & medicinal chemistry letters JID - 9107377 RN - 0 ((3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide) RN - 0 (Benzofurans) RN - 0 (Chelating Agents) RN - 0 (Isotopes) RN - 0 (Quinolines) RN - 60YU5MIG9W (Thorium) SB - IM MH - Animals MH - Benzofurans MH - Chelating Agents/chemical synthesis/*chemistry/pharmacokinetics/pharmacology MH - Female MH - Heart/drug effects MH - Isotopes MH - Lung/drug effects MH - Mice MH - Molecular Structure MH - Quinolines MH - Thorium/*chemistry/pharmacokinetics/pharmacology OTO - NOTNLM OT - 3-hydroxy-N-methyl-2-pyridinone OT - Chelator OT - Me-3,2-HOPO OT - Targeted Thorium Conjugates (TTCs) OT - Thorium-227 (Th-227) EDAT- 2016/08/01 06:00 MHDA- 2017/08/30 06:00 CRDT- 2016/08/01 06:00 PHST- 2016/06/08 00:00 [received] PHST- 2016/07/14 00:00 [revised] PHST- 2016/07/15 00:00 [accepted] PHST- 2016/08/01 06:00 [entrez] PHST- 2016/08/01 06:00 [pubmed] PHST- 2017/08/30 06:00 [medline] AID - S0960-894X(16)30747-8 [pii] AID - 10.1016/j.bmcl.2016.07.034 [doi] PST - ppublish SO - Bioorg Med Chem Lett. 2016 Sep 1;26(17):4318-21. doi: 10.1016/j.bmcl.2016.07.034. Epub 2016 Jul 17.