Near-infrared fluorescence lifetime pH-sensitive probes |
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Authors: | Berezin Mikhail Y Guo Kevin Akers Walter Northdurft Ralph E Culver Joseph P Teng Bao Vasalatiy Olga Barbacow Kyle Gandjbakhche Amir Griffiths Gary L Achilefu Samuel |
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Affiliation: | †Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;‡Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri;§Imaging Probe Development Center, National Heart, Lung, and Blood Institute, Bethesda, Washington, District of Columbia;¶Physical Biology Program, Eunice Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Washington, District of Columbia |
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Abstract: | We report what we believe to be the first near-infrared pH-sensitive fluorescence lifetime molecular probe suitable for biological applications in physiological range. Specifically, we modified a known fluorophore skeleton, hexamethylindotricarbocyanine, with a tertiary amine functionality that was electronically coupled to the fluorophore, to generate a pH-sensitive probe. The pKa of the probe depended critically on the location of the amine. Peripheral substitution at the 5-position of the indole ring resulted in a compound with pKa ∼ 4.9 as determined by emission spectroscopy. In contrast, substitution at the meso-position shifted the pKa to 5.5. The resulting compound, LS482, demonstrated steady-state and fluorescence-lifetime pH-sensitivity. This sensitivity stemmed from distinct lifetimes for protonated (∼1.16 ns in acidic DMSO) and deprotonated (∼1.4 ns in basic DMSO) components. The suitability of the fluorescent dyes for biological applications was demonstrated with a fluorescence-lifetime tomography system. The ability to interrogate cellular processes and subsequently translate the findings in living organisms further augments the potential of these lifetime-based pH probes. |
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