A Ln(III)-3-hydroxypyridine pH responsive probe optimized by DFT.

Michael A. Caldwell,Thomas J. Meade,Christopher R. Brue,Tyler J. Whittemore

doi:10.1039/c9ra11058e

Abstract

Differences in tissue pH can be diagnostic of cancer and other conditions that shift cell metabolism. Paramagnetic probes are promising tools for pH mapping in vivo using magnetic resonance spectroscopy (MRS) as they provide uniquely shifted MR signals that change with pH. Here, we demonstrate a 3-hydroxy-6-methylpyridyl coordinating group as a new pH-responsive reporter group for Ln(iii) MRS probes. The pH response of the complex was observed by UV-Vis, fluorescence, and NMR spectroscopies, and modeled using DFT. These results provide insight into the observed pH-dependent NMR spectrum of the complex. The protonation state of the hydroxypyridine changes the coordinating ability of the ligand, affecting the dipolar field of the lanthanide and the chemical shift of nearby reporter nuclei. The favorable pH response and coordination properties of the 3-hydroxypyridyl group indicate its potential for further development as a dual responsive-reporter group. Incorporation into optimized scaffolds for MRS detection may enable sensitive pH-mapping in vivo.

Highlights

Dysregulation of extracellular pH is a hallmark of solid tumors and in ammation
Monitoring and mapping pH in vivo provides an important tool to detect, monitor, and treat these conditions, and signi cant advances have been made in recent decades developing optical and magnetic resonance (MR) probes to measure extracellular pH.[4,5,6,7,8,9,10]
MR spectroscopy (MRS) techniques are increasingly utilized for these applications because they can non-invasively examine pH-dependent signals of an array of metabolites and probes with high spatial and spectral resolution.[5,6,11]

Summary

Introduction

Dysregulation of extracellular pH is a hallmark of solid tumors and in ammation. In a solid tumor, poor vascularization and metabolic changes lead to anoxia and the accumulation of anaerobic metabolites, decreasing the local pH.[1,2] In ammatory signaling and decreased pH in the tumor microenvironment have been shown to limit the efficacy of the immune response and to accelerate metastatic and invasive potential.[2,3] Directly monitoring and mapping pH in vivo provides an important tool to detect, monitor, and treat these conditions, and signi cant advances have been made in recent decades developing optical and magnetic resonance (MR) probes to measure extracellular pH.[4,5,6,7,8,9,10] MR spectroscopy (MRS) techniques are increasingly utilized for these applications because they can non-invasively examine pH-dependent signals of an array of metabolites and probes with high spatial and spectral resolution.[5,6,11]Paramagnetic metals, lanthanides, impute valued properties for MR probes. Dysregulation of extracellular pH is a hallmark of solid tumors and in ammation. Interactions with the unpaired spins of the metal reduce magnetic relaxation times and impact the resonant frequencies of nearby nuclei producing unique signals.[9,12,13,14,15] These properties have been applied to monitor solution pH through relaxometry,[12,16,17] paramagnetic chemical exchange saturation transfer (paraCEST),[13,18,19,20] and chemical

Methods

Results

Conclusion