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Open AccessArticle

The Influence of the Combination of Carboxylate and Phosphinate Pendant Arms in 1,4,7-Triazacyclononane-Based Chelators on Their 68Ga Labelling Properties

1
Department of Nuclear Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98, H-4032 Debrecen, Hungary
2
Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Walther-Meissner-Strasse 3, D-85748 Garching, Germany
3
Department of Inorganic Chemistry, Charles University in Prague, Hlavova 2030, 12840 Prague 2, Czech Republic
*
Author to whom correspondence should be addressed.
Current address: Scintomics GmbH, Lindach 4, Fürstenfeldbruck 82256, Germany.
Academic Editor: Svend Borup Jensen
Molecules 2015, 20(7), 13112-13126; https://doi.org/10.3390/molecules200713112
Received: 10 May 2015 / Revised: 10 July 2015 / Accepted: 13 July 2015 / Published: 21 July 2015
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
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. View Full-Text
Keywords: positron emission tomography; metal complexes; macrocyclic ligands; radiopharmaceuticals; tacn derivative; phosphinate complexes; gallium complexes; radiolabelling; PET tracer development; molecular imaging positron emission tomography; metal complexes; macrocyclic ligands; radiopharmaceuticals; tacn derivative; phosphinate complexes; gallium complexes; radiolabelling; PET tracer development; molecular imaging
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Máté, G.; Šimeček, J.; Pniok, M.; Kertész, I.; Notni, J.; Wester, H.-J.; Galuska, L.; Hermann, P. The Influence of the Combination of Carboxylate and Phosphinate Pendant Arms in 1,4,7-Triazacyclononane-Based Chelators on Their 68Ga Labelling Properties. Molecules 2015, 20, 13112-13126.

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