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A Frequency-Selective pH-Responsive paraCEST Agent.

ABSTRACT: Paramagnetic chemical exchange saturation transfer (paraCEST) agents are well-suited for imaging tissue pH because the basis of CEST, chemical exchange, is inherently sensitive to pH. Several previous pH-sensitive paraCEST agents were based on an exchanging Ln³⁺ -bound water molecule as the CEST antenna but this design often added additional line-broadening to the bulk water signal due to T₂ exchange. We report herein a pH-sensitive paraCEST agent that lacks an inner-sphere water molecule but contains one Ln-bound -OH group for CEST activation. The Yb³⁺ complex, Yb(1), displayed a single, highly shifted CEST peak originating from the exchangeable Yb-OH proton, the frequency of which changed over the biologically relevant pH range. CEST images of phantoms ranging in pH from 6 to 8 demonstrate the potential of this agent for imaging pH. Initial rodent imaging studies showed that Gd(1) remains in the vascular system much longer than anticipated but is cleared slowly via renal filtration.

SUBMITTER: Ratnakar SJ

PROVIDER: S-EPMC7719596 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ln(S-THP)(3+) complexes are paramagnetic chemical exchange saturation transfer (PARACEST) agents for magnetic resonance imaging (MRI; S-THP = (1S,4S,7S,10S)-1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane, Ln(III) = Ce(III), Eu(III), Yb(III)). CEST spectra at 11.7 T show that the PARACEST effect of these complexes is enhanced at neutral pH in buffered solutions containing 100 mM NaCl upon the addition of 1-2 equiv of diethylphosphate (DEP). CEST images of phantoms at 4.7 T confirm that DEP enhances the properties of Yb(S-THP)(3+) as a PARACEST MRI agent in buffered solutions at neutral pH and 100 mM NaCl. Studies using (1)H NMR, direct excitation Eu(III) luminescence spectroscopy, and UV-visible spectroscopy show that DEP is an outersphere ligand. Dissociation constants for [Ln(S-THP)(OH(2))](DEP) are 1.9 mM and 2.8 mM for Ln(III) = Yb(III) at pH 7.0 and Eu(III) at pH 7.4. Related ligands including phosphorothioic acid, O,O-diethylester, ethyl methylphosphonate, O-(4-nitrophenylphosphoryl)choline, and cyclic 3,5-adenosine monophosphate do not activate PARACEST. BNPP (bis(4-nitrophenyl phosphate) activates PARACEST of Ln(S-THP)(3+) (Ln(III) = Eu(III), Yb(III)), albeit less effectively than does DEP. These data show that binding through second coordination sphere interactions is selective for phosphate diesters with two terminal oxygens and two identical ester groups. A crystal structure of [Eu(S-THP)(OH(2))]((O(2)NPhO)(2)PO(2))(2)(CF(3)SO(3)) x 2 H(2)O x iPrOH has two outersphere BNPP anions that form hydrogen bonds to the alcohol groups of the macrocycle and the bound water ligand. This structure supports (1)H NMR spectroscopy studies showing that outersphere interactions of the phosphate diester with the alcohol protons modulate the rate of alcohol proton exchange to influence the PARACEST properties of the complex. Further, DEP interacts only with the nonionized form of the complex, Ln(S-THP)(OH(2))(3+) contributing to the pH dependence of the PARACEST effect.

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A Frequency-Selective pH-Responsive paraCEST Agent.

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