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A coordination cage containing six high-spin Fe(iii) centers is an effectiveT₁relaxation agent through second-sphere water interactions. The cage is robust towards dissociation and binds avidly to serum albumin through electrostatic interactions. 

Fe(iii) macrocyclic complexes with mixed oxygen donor pendants are studied as T₁MRI probes. Complexes with a phenolate pendant are among the most promising and produce pH dependent relaxivity profiles consistent with proton exchange pathways. 

Liposomes containing high-spin Fe(iii ) coordination complexes were prepared towards the production of T 1 MRI probes with improved relaxivity. The amphiphilic Fe( iii) complexes were anchored into the liposome with two alkyl chains to give a coordination sphere containing mixed amide and hydroxypropyl pendant groups. The encapsulated complex contains a macrocyclic ligand with three phosphonate pendants, [Fe(NOTP)] 3−, which was chosen for its good aqueous solubility. Four types of MRI probes were prepared including those with intraliposomal Fe(iii) complex (LipoA) alone, amphiphilic Fe(iii) complex (LipoB), both intraliposomal and amphiphilic complex (LipoC) or micelles formed with amphiphilic complex. Water proton relaxivities r 1 and r 2 were measured and compared to a small molecule macrocyclic Fe(iii) complex containing similar donor groups. Micelles of the amphiphilic Fe( iii) complex had proton relaxivity values ( r 1 = 2.6 mM−1 s −1 ) that were four times higher than the small hydrophilic analog. Liposomes with amphiphilic Fe(iii) complex (LipoB) have a per iron relaxivity of 2.6 mM −1 s −1 at pH 7.2, 34 °C at 1.4 T whereas liposomes containing both amphiphilic and intraliposomal Fe(iii) complexes (lipoC) have r 1 of 0.58 mM −1 s −1 on a per iron basis consistent with quenching of the interior Fe(iii) complex relaxivity. Liposomes containing only encapsulated [Fe(NOTP)]3− have a lowered r 1 of 0.65 mM−1s −1 per iron complex. Studies show that the biodistribution and clearance of the different types liposomal nanoparticles differ greatly. LipoB is a blood pool agent with a long circulation time whereas lipoC is cleared more rapidly through both renal and hepatobiliary pathways. These clearance differences are consistent with lower stability of LipoC compared to LipoB. 

Co( ii ) complexes of 1,4,7,10-tetraazacyclododecane (CYCLEN) or 1,4,8,11-tetraazacyclotetradecane (CYCLAM) with 2-hydroxypropyl or carbamoylmethyl (amide) pendants are studied with the goal of developing paramagnetic chemical exchange saturation transfer (paraCEST) agents. Single-crystal X-ray diffraction studies show that two of the coordination cations with hexadentate ligands, [Co(DHP)] 2+ and [Co(BABC)] 2+ , form six-coordinate complexes; whereas two CYCLEN-based complexes with potentially octadentate ligands, [Co(THP)] 2+ and [Co(HPAC)] 2+ , are seven-coordinate with only three of the four pendant groups bound to the metal center. 1 H NMR spectra of these complexes suggest that the six-coordinate complexes are present as a single isomer in aqueous solution. For the complexes which are seven-coordinate in the solid state, one is highly fluxional in aqueous solution on the NMR time scale ([Co(HPAC)] 2+ ), whereas the NMR spectrum of [Co(THP)] 2+ is consistent with an eight-coordinate complex with all pendants bound. Co( ii ) complexes of CYCLEN derivatives show CEST effects of low intensity that are assigned to NH or OH groups of the pendants. One complex, [Co(DHP)] 2+ , shows a highly-shifted CEST peak at 113 ppm versus bulk water, attributed to OH protons. However, the CEST effect is largest for two Co( ii ) CYCLAM-based complexes with coordinated amide groups that undergo NH proton exchange. All five complexes are inert towards dissociation in buffered solutions containing carbonate and phosphate and towards trans-metalation by excess Zn( ii ). These data give insight into the production of an intense CEST effect for tetraazamacrocyclic complexes with pendant groups containing NH or OH exchangeable protons. The intense and highly shifted CEST peak(s) of the CYCLAM-based complexes suggest that they are promising for further development as paraCEST agents.