title: Facile synthesis and evaluation of C-functionalized benzyl-1-oxa-4,7,10-triazacyclododecane-N,N',N″-triacetic acid as chelating agent for ¹¹¹In-labeled polypeptides.
abstract: A 12-membered polyazamacrocycle, 1-oxa-4,7,10-triazacyclododecane-N,N',N″-triacetic acid (ODTA), has been reported to provide an indium chelate of net neutral charge with thermodynamic stability higher than 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA). However, neither synthetic procedure for a C-functionalized ODTA (C-ODTA) nor its chelating ability with a trace amount of radioactive indium-111 ((111)In) has been elucidated. We herein present a facile synthetic procedure for C-ODTA, and estimated its ability as a chelating agent for radiolabeling peptides and proteins with (111)In. The synthetic procedure involves the synthesis of a linear precursor using a para-substituted phenylalanine derivative as a starting material. The following intramolecular cyclization reaction was best performed (>73% yield) when Boc-protected linear compound and the condensation reagent, HATU, were simultaneously added to the reaction vessel at the same flow rate. The cyclic compound was then reduced with BH(3) and alkylated with tert-butyl bromoacetate. The synthetic procedure was straightforward and some optimization would be required. However, most of the intermediate compounds were obtained easily in good yields, suggesting that the present synthetic procedure would be useful to synthesize C-ODTA derivatives. The intramolecular cyclization reaction might also be applicable to synthesize polyazamacrocycles of different ring sizes and cyclic peptides. In (111)In radiolabeling reactions, C-ODTA provided (111)In chelates in higher radiochemical yields at low ligand concentrations when compared with C-DOTA. The (111)In-labeled C-ODTA remained unchanged in the presence of apo-transferrin. The biodistribution studies also showed that the (111)In-labeled compound was mainly excreted into urine as intact. These findings indicate that C-ODTA would be useful to prepare (111)In-labeled peptides of high specific activities in high radiochemical yields.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Ayaka
authors.initials: A
authors.lastname: Kanai
authors.forename: Tomoya
authors.initials: T
authors.lastname: Uehara
authors.forename: Francisco L
authors.initials: FL
authors.lastname: Guerra Gomez
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hanaoka
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Arano
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D002614:Chelating Agents / Q000737:chemistry*; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D003500:Cyclization; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D007205:Indium Radioisotopes / Q000737:chemistry; D007275:Injections, Intravenous; D007553:Isotope Labeling; D051379:Mice; D010455:Peptides / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: C572010:1-oxa-4,7,10-triazacyclododecane-N,N'',N'''-triacetic acid; C572011:6-(4-nitrobenzyl)-1-oxa-4,7,10-triazacyclododecane-N,N'',N'''-triacetic acid; D000085:Acetates; D002614:Chelating Agents; D056831:Coordination Complexes; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D010455:Peptides