Design and synthesis of selective manganese(II) chelators

Department of Inorganic ChemistryKatedra anorganické chemieFaculty of SciencePřírodovědecká fakult

Macrobicyclic ligands for use in MRI

4 Title: Macrobicyclic ligands for use in MRI Author: Bc. Miroslav Pniok Department: Department of Inorganic Chemistry, Faculty of Science Supervisor: doc. RNDr. Jan Kotek, Ph.D. Supervisor's e-mail address: [email protected] Abstract: The aim of this project is to synthesize new kind of macrobicyclic ligands for Ln3+ ions, especially Gd3+ ion. Gadolinium(III) complexes are widely used in the clinical practice as contrast agents for MR imaging and an improvement of their properties is in the center of interest of many scientific teams. The macrobicyclic ligands have been designed to make possible coordination of two water molecules in the first coordination sphere with fast water exchange. The macrocyclic core (cyclen) is combined with a linking phosphinate chain in N1 ,N4 - and N1 ,N7 -positions forming a cryptand-like structure. The N1 ,N7 -isomer Et2L1 was synthesized in a small amount so only the N1 ,N4 -isomer H2L3 has been studied. The protonation constants have been determined by pH 31 P NMR titration. Keywords: cyclen, chelating agent, cryptand, MRI, phosphinat

Mn2+ complexes of 1-oxa-4,7-diazacyclononane based ligands with acetic, phosphonic and phosphinic acid pendant arms: Stability and relaxation studies

International audienceA new class of macrocyclic ligands based on 1-oxa-4,7-diazacyclononane was synthesized and their Mn2+ complexes were investigated with respect to stability and relaxation properties. Each ligand has two pendant arms involving carboxylic (H2L1 - 1-oxa-4,7-diazacyclononane-4, 7-diacetic acid), phosphonic (H4L2 - 1-oxa-4,7- diazacyclononane-4,7-bis(methylenephosphonic acid)), phosphinic (H 2L3 - 1-oxa-4,7-diazacyclononane-4,7- bis(methylenephosphinic acid)) or phenylphosphinic (H2L4 - 1-oxa-4,7-diazacyclononane-4,7-bis[methylene(phenyl)phosphinic acid]) acid moieties. H2L3 and H2L4 were synthesized for the first time. The crystal structure of the Mn2+ complex with H2L4 confirmed a coordination number of 6 for Mn2+. The protonation constants of all ligands and the stability constants of their complexes with Mn2+ and some biologically or biomedically relevant metal ions were determined by potentiometry. The protonation sequence of H2L3 was followed by 1H and 31P NMR titration and the second protonation step was attributed to the second macrocyclic nitrogen atom. The potentiometric data revealed a relatively low thermodynamic stability of the Mn2+ complexes with all ligands investigated. For H2L3 and H2L 4, full Mn2+ complexation cannot be achieved even with 100% ligand excess. The transmetallation of MnL1 and MnL2 with Zn2+ was too fast to be followed at pH 6. Variable temperature 1H NMRD and 17O NMR measurements have been performed on MnL1 and MnL2 to provide information on water exchange and rotational dynamics. The 17O chemical shifts indicate hydration equilibrium between mono- and bishydrated species for MnL1, while MnL2 is monohydrated. The water exchange is considerably faster on MnL1 (kex298 = 1.2 × 109 s-1) than on MnL2 (kex298 = 1.2 × 107 s-1). Small endogenous anions (phosphate, carbonate, citrate) do not replace the coordinated water in either of the complexes, but they induce their slow decomposition. All Mn2+ complexes are stable toward air-oxidation

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

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

Scandium(III) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with 44 Sc from cyclotron and from a 44 Ti/ 44 Sc generator †

International audienceThe complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylene-phosphinic (DO3AP PrA and DO3AP ABn) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(III) complexes were determined by potentiometry combined with 45 Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc–DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(III) precludes stability constant determination of the Sc–DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless , as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with 44 Sc was performed using the radioisotope from two sources, a 44 Ti/ 44 Sc generator and 44m Sc/ 44 Sc from a cyclotron. The best radio-labelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(III) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of 44 Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the 44 Sc–DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine