Richard B. Dorshow,1 Bethel Asmelash,1 Lori K. Chinen,1 Martin P. Debreczeny,1 Richard M. Fitch,1 John N. Freskos,1 Karen P. Galen,1 Kimberly R. Gaston,1 Timothy A. Marzan,1 Amruta R. Poreddy,1 Raghavan Rajagopalan,1 Jeng-Jong Shieh,1 William L. Neumann1
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The ability to continuously monitor renal function via the glomerular filtration rate (GFR) in the clinic is currently an
unmet medical need. To address this need we have developed a new series of hydrophilic fluorescent probes designed
to clear via glomerular filtration for use as real time optical monitoring agents at the bedside. The ideal molecule should
be freely filtered via the glomerular filtration barrier and be neither reabsorbed nor secreted by the renal tubule. In
addition, we have hypothesized that a low volume of distribution into the interstitial space could also be advantageous.
Our primary molecular design strategy employs a very small pyrazine-based fluorophore as the core unit. Modular
chemistry for functionalizing these systems for optimal pharmacokinetics (PK) and photophysical properties have been
developed. Structure-activity relationship (SAR) and pharmacokinetic (PK) studies involving hydrophilic pyrazine
analogues incorporating polyethylene glycol (PEG), carbohydrate, amino acid and peptide functionality have been a
focus of this work. Secondary design strategies for minimizing distribution into the interstitium while maintaining
glomerular filtration include enhancing molecular volume through PEG substitution. In vivo optical monitoring
experiments with advanced candidates have been correlated with plasma PK for measurement of clearance and hence
GFR.
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Richard B. Dorshow, Bethel Asmelash, Lori K. Chinen, Martin P. Debreczeny, Richard M. Fitch, John N. Freskos, Karen P. Galen, Kimberly R. Gaston, Timothy A. Marzan, Amruta R. Poreddy, Raghavan Rajagopalan, Jeng-Jong Shieh, William L. Neumann, "New optical probes for continuous monitoring of renal function," Proc. SPIE 6867, Molecular Probes for Biomedical Applications II, 68670C (22 February 2008); https://doi.org/10.1117/12.763697