Fluorescence-enhanced europium complexes for the assessment of renal function

Chinen, Lori K.; Galen, Karen P.; Kuan, K. T.; Dyszlewski, Mary; Ozaki, Hiroaki; Sawai, Hiroaki; Pandurangi, Raghootama S.; Jacobs, Frederick G.; Dorshow, Richard B.; Rajagopalan, Raghavan

doi:10.1117/12.763665

Cited by 3 publications

(16 citation statements)

References 16 publications

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“…However, the infrequently used conventional GFR agents such as inulin, iothalamate, , and 99 m Tc-DTPA suffer from various undesirable properties (such as radioactivity, need for ionizing radiation, laborious ex-vivo handling of blood and urine samples, and lack of consistent and reliable supply) that render them unsuitable for real-time point-of-care renal function monitoring. Thus, to overcome these various limitations, there has been considerable effort directed at developing fluorescent GFR tracer agents. − …”

Section: Introductionmentioning

confidence: 99%

Hydrophilic Pyrazine Dyes as Exogenous Fluorescent Tracer Agents for Real-Time Point-of-Care Measurement of Glomerular Filtration Rate

et al. 2011

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Various hydrophilic pyrazine-bis(carboxamides) derived from 3,5-diamino-pyrazine-2,5-dicarboxylic acid bearing neutral and anionic groups were prepared and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, the dianionic d-serine pyrazine derivatives 2d and 2j, and the neutral dihydroxypropyl 2h, exhibited favorable physicochemical and clearance properties. In vitro studies show that 2d, 2h, and 2j have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that these three compounds exhibit a plasma clearance equivalent to iothalamate (a commonly considered gold standard GFR agent). In addition, these compounds have a higher urine recovery compared to iothalamate. Finally, the plasma clearance of 2d, 2h, and 2j remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration only. Hence, 2d, 2h, and 2j are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR.

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Section: Introductionmentioning

confidence: 99%

Hydrophilic Pyrazine Dyes as Exogenous Fluorescent Tracer Agents for Real-Time Point-of-Care Measurement of Glomerular Filtration Rate

et al. 2011

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“…7 To overcome some of the limitations such as laborious ex-vivo handling of blood and urine samples and use and disposal of radioactivity, considerable effort has been directed at developing fluorescent GFR agents that can be utilized for real-time point-of-care monitoring of renal function. [8][9][10][11] withdrawing groups at 2,5-positions strongly absorb and emit in the blue to orange regions of the electromagnetic spectrum with large Stokes' shift. The extreme insolubility of most of these known dyes in aqueous media renders them unsuitable for development as GFR tracers.…”

Section: Introductionmentioning

confidence: 99%

Development of fluorescent tracers for the real-time monitoring of renal function

et al. 2011

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Accurate measurement of glomerular filtration rate (GFR) at the bedside is highly desirable in order to assess renal function in real-time, which is currently an unmet clinical need. In our pursuit to develop exogenous fluorescent tracers as GFR markers, various hydrophilic derivatives of 3,6-diaminopyrazine-2,5-dicarboxylic acid with varying molecular weights and absorption/emission characteristics were synthesized. These include polyhydroxyalkyl based small molecules and poly(ethylene glycol) (PEG) substituted moderate molecular weight compounds, which were further subgrouped into analogs having blue excitation with green emission, and relatively longer wavelength analogs having green excitation with orange emission. Lead compounds were identified in each of the four classes on the basis of structureactivity relationship studies, which included in vitro plasma protein binding, in vivo urine recovery of administered dose, and in vivo optical monitoring. The in vivo optical monitoring experiments with lead candidates have been correlated with plasma pharmacokinetic (PK) data for measurement of clearance and hence GFR. Renal clearance of these compounds, occurring exclusively via glomerular filtration, was established by probenecid blocking experiments. The renal clearance property of all these advanced candidates was superior to that of the iothalamate, which is currently an accepted standard for the measurement of GFR.

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“…[31][32][33][34][35][36][37] The key requirements for an ideal fluorescent tracer agent are: (a) must be excited at and emit in the visible region ( ≥ ~425 nm); (b) must be highly hydrophilic; (c) must be either neutral or anionic; (c) must have very low or no plasma protein binding; (d) must not be metabolized in vivo, and (e) must clear exclusively via glomerular filtration as demonstrated by equality of plasma clearance with and without a tubular secretion inhibitor such as probenecid. 38 The selection of the lead clinical candidate(s) may be based on secondary considerations such as the ease of synthesis, lack of toxicity, and stability.…”

Section: Development Of Fluorescent Tracer Agentsmentioning

confidence: 99%

“…The first method involves enhancing the fluorescence of known renal agents that are intrinsically poor emitters such as lanthanide metal complexes; and the second involves transforming highly fluorescent dyes (which are intrinsically lipophilic) into hydrophilic, anionic species to force them to clear via the kidneys. 32 In the first approach, several europium-DTPA complexes endowed with various molecular 'antenna' to induce ligand-to-metal fluorescence resonance energy transfer (FRET) were prepared and tested. 32 Some of metal complexes (e.g.…”

Section: Development Of Fluorescent Tracer Agentsmentioning

confidence: 99%

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Exogenous Fluorescent Agents for the Determination of Glomerular Filtration Rate

Rajagopalan¹,

Dorshow²

2012

Chronic Kidney Disease

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Fluorescence-enhanced europium complexes for the assessment of renal function

Cited by 3 publications

References 16 publications

Hydrophilic Pyrazine Dyes as Exogenous Fluorescent Tracer Agents for Real-Time Point-of-Care Measurement of Glomerular Filtration Rate

Hydrophilic Pyrazine Dyes as Exogenous Fluorescent Tracer Agents for Real-Time Point-of-Care Measurement of Glomerular Filtration Rate

Development of fluorescent tracers for the real-time monitoring of renal function

Exogenous Fluorescent Agents for the Determination of Glomerular Filtration Rate

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