Iron(II) PARACEST MRI Contrast Agents

Abstract

The first examples of Fe(II) PARACEST magnetic resonance contrast agents are reported (PARACEST = paramagnetic chemical exchange saturation transfer). The iron(II) complexes contain a macrocyclic ligand, either 1,4,7-tris(carbamoylmethyl)-1,4,7-triazacyclononane (L1) or 1,4,7-tris[(5-amino-6-methyl-2-pyridyl)methyl]-1,4,7-triazacyclononane (L2). The macrocycles bind Fe(II) in aqueous solution with formation constants of log K = 15.6 and 19.2, respectively and maintain the Fe(II) state in the presence of air. These complexes each contain six exchangeable protons for CEST which are amide protons in [Fe(L1)]2+ or amino protons in [Fe(L2)]2+. The CEST peak for the [Fe(L1)]2+ amide protons is at 69 ppm downfield of the bulk water resonance whereas the CEST peak for the [Fe(L2)]2+ amine protons is at 6 ppm downfield of bulk water. CEST imaging using a MRI scanner shows that the CEST effect can be observed in solutions containing low millimolar concentrations of complex at neutral pH, 100 mM NaCl, 20 mM buffer at 22 °C or 37 °C.

The reactivity of macrocyclic Fe(II) paraCEST MRI contrast agents towards biologically relevant anions, cations, oxygen or peroxide

“…1). [Fe(L1)] 2+ shows three broad proton resonances assigned to non-exchangeable protons and two sharper proton resonances assigned to the two chemically distinguishable protons of the amide groups [1]. Similarly, [Fe(L4)] 2+ in CD 3 CN shows six broad resonances attributed to the non-exchangeable protons of the macrocycle and two sharp proton resonances for the amide protons (Fig.…”

“…The Evans' method was used to determine magnetic susceptibility in solution and magnetic moments were calculated as reported previously [1]. Samples were prepared using a coaxial NMR insert which contained the diamagnetic standard of 5% tert-butanol in D 2 O.…”

“…Work in our laboratory has recently shown that high spin Fe(II) complexes are promising as paramagnetic chemical exchange saturation transfer (paraCEST) MRI contrast agents [1,2]. ParaCEST MRI contrast agents are members of a relatively new class of contrast agents that generate signal changes through chemical exchange saturation transfer (CEST) [3].…”

Iron(III) Contrast Agent Candidates for MRI: a Survey of the Structure–Effect Relationship in the Last 15 ­Years of Studies

“…[43] Chemical exchange saturation transfer (CEST) methods caused by paramagnetic species enable the alteration (even extinction) of water signals. [87] Another group in the new field of development of iron CAs is the application of nanomaterials. Although superparamagnetic particles of iron oxides (SPIOs) are a well-established group of approved CAs, [88] rapid development in the formation and modification of various nanomaterials has also become an attractive field for imaging.…”

Proton Chemical Exchange Saturation Transfer (CEST) MRS and MRI

“…Three recent dedicated CEST workshops (3rd, 4th, and 5th international CEST workshops in Annapolis, 2012, Torino, 2014, and Philadelphia 2016) drew about 90-200 registrants. The last decade has shown major developments for paraCEST agents, 14,15,20,89,90,119,[135][136][137][138][139][140][141][142][143][144][145][146][147][148] diaCEST agents, 12,13,17,42,43,68,72,88,102,116,125,128,[149][150][151][152][153][154][155][156][157][158][159][160] and even hyperpolarized (hyperCEST) agents. 161,162 This is not surprising in view of the number of potential applications including pH imaging, metabolite detection, ion detection, cellular protein and peptide imaging, cell labeling, temperature i...…”