title: The influence of the combination of carboxylate and phosphinate pendant arms in 1,4,7-triazacyclononane-based chelators on their 68Ga labelling properties.
abstract: In order to compare the coordination properties of 1,4,7-triazacyclononane (tacn) derivatives bearing varying numbers of phosphinic/carboxylic acid pendant groups towards 68Ga, 1,4,7-triazacyclononane-7-acetic-1,4-bis(methylenephosphinic) acid (NOPA) and 1,4,7- triazacyclononane-4,7-diacetic-1-[methylene(2-carboxyethyl)phosphinic] acid (NO2AP) were synthesized using Mannich reactions with trivalent or pentavalent forms of H-phosphinic acids as phosphorus components. Stepwise protonation constants logK1-3 12.06, 3.90 and 1.95, and stability constants with GaIII and CuII, logKGaL 24.01 and logKCuL 16.66, were potentiometrically determined for NOPA. Both ligands were labelled with 68Ga and compared with NOTA (tacn-N,N',N″-triacetic acid) and NOPO, a TRAP-type [tacn-N,N',N″- tris(methylenephosphinic acid)] chelator. At pH 3, NOPO and NOPA showed higher labelling efficiency (binding with lower ligand excess) at both room temperature and 95 °C, compared to NO2AP and NOTA. Labelling efficiency at pH = 0-3 correlated with a number of phosphinic acid pendants: NOPO >> NOPA > NO2AP >> NOTA; however, it was more apparent at 95 °C than at room temperature. By contrast, NOTA was found to be labelled more efficiently at pH > 4 compared to the ligands with phosphinic acids. Overall, replacement of a single phosphinate donor with a carboxylate does not challenge 68Ga labelling of TRAP-type chelators. However, the presence of carboxylates facilitates labelling at neutral or weakly acidic pH.
authors.affiliation: Department of Nuclear Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98, H-4032 Debrecen, Hungary. mate.gabor@med.unideb.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Máté
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Walther-Meissner-Strasse 3, D-85748 Garching, Germany.
authors.forename: Jakub
authors.initials: J
authors.lastname: Šimeček
authors.affiliation: Department of Inorganic Chemistry, Charles University in Prague, Hlavova 2030, 12840 Prague 2, Czech Republic. mirekpniok@gmail.com.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Pniok
authors.affiliation: Department of Nuclear Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98, H-4032 Debrecen, Hungary. kertesz.istvan@med.unideb.hu.
authors.forename: István
authors.initials: I
authors.lastname: Kertész
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Walther-Meissner-Strasse 3, D-85748 Garching, Germany. johannes.notni@tum.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Notni
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Walther-Meissner-Strasse 3, D-85748 Garching, Germany. h.j.wester@tum.de.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.affiliation: Department of Nuclear Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98, H-4032 Debrecen, Hungary. galuska.laszlo@med.unideb.hu.
authors.forename: László
authors.initials: L
authors.lastname: Galuska
authors.affiliation: Department of Inorganic Chemistry, Charles University in Prague, Hlavova 2030, 12840 Prague 2, Czech Republic. petrh@natur.cuni.cz.
authors.forename: Petr
authors.initials: P
authors.lastname: Hermann
mesh_terms: D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry; D005708:Gallium / Q000737:chemistry*; D005710:Gallium Radioisotopes / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D005710:Gallium Radioisotopes; D006571:Heterocyclic Compounds; C075712:1,4,7-triazacyclononane; D005708:Gallium
keywords: PET tracer development; gallium complexes; macrocyclic ligands; metal complexes; molecular imaging; phosphinate complexes; positron emission tomography; radiolabelling; radiopharmaceuticals; tacn derivative