The past decade has seen a 30% increase in chronic kidney disease, which now affects an estimated 27 million Americans and accounts for more than 24% of all Medicare costs. Effective strategies are urgently needed to detect early renal disease, monitor the course of therapy, retard progression, and enhance diagnostic accuracy. To meet these needs, our primary objective is to complete the development and initial human evaluation of novel anionic 99mTc based probes for the non-invasive, cost effective, accurate, and reproducible measure of effective renal plasma flow (ERPF). 131I-ortho-iodohippuran (OIH), the clinical standard for measuring the ERPF, is no longer commercially available and 99mTc-mercaptoacetyltriglycine (MAG3), the best FDA approved agent using widely available 99mTc, has serious limitations. The MAG3 clearance is only 50-60% that of OIH, does not measure a standard renal functional parameter, and cannot reliably detect a change in renal function less than 35%. The feasibility of our approach is demonstrated by the fact that our NIH program has already led to (1) the identification of the best first-generation 99mTcO renal tracers: MAG3, DD-EC, syn-D-MAEC;(2) new 99mTc(CO)3 tracers including the highly promising 99mTc(CO)3 nitrilotriacetic acid (NTA) tracer;(3) one patent;(4) a provisional patent, and (5) the first 99mTc(CO)3 renal tracer to be evaluated in humans. 99mTc(CO)3 (NTA) is a single species, is amenable to kit formulation and has a clearance equivalent to 131I-OIH based on studies in five volunteers. An important second objective is to advance Tc and Re (rhenium) chemistry and ligand design, which the process of achieving our primary objective will accomplish. Specifically, we propose to (1) prepare novel tracers amenable to kit formulation by focusing on ligands that advance the chemistry of the {Tc(I)(CO)3}+ core, with innovative ligand design and powerful solution speciation methods applied to Re analogs especially where the donor groups favor a single preferably non-chiral 99mTc anionic agent;(2) determine the pharmacokinetics of each new tracer, especially the rate and specificity of renal excretion in streamlined animal models;(3) determine the pharmacokinetics and dosimetry in humans and use the results to enhance tracer design;and (4) conduct focused human studies comparing image quality of NTA (and other suitable tracers) with OIH and MAG3 in relevant patient populations. A superior ERPF tracer will (1) enhance diagnostic accuracy, particularly in azotemic pediatric and adult patients with suspected obstruction, (2) provide a simple, accurate test to detect and monitor changes in tubular function, (3) assist the diagnosis and care of patients with prerenal azotemia, (4) facilitate basic and clinical research for the detection of early tubular dysfunction and the prevention of renal disease, and (5) aid others in developing non-renal 99mTc diagnostic tracers and 2-emitting 186Re and 188Re therapeutic agents, because our agents are specifically designed to avoid the high kidney retention plaguing Re therapeutic agents. We are close to success and anticipate that the next funding period will bring this project to completion.

Public Health Relevance

The past decade has seen a 30 percent increase in chronic kidney disease which now affects an estimated 27 million Americans and accounts for more than 24% of all Medicare costs. To improve the treatment of patients with known or suspected renal disease and to support basic and clinical research into the mechanisms of renal tubular function and the prevention of renal disease, our primary objective is to develop a new radioactive tracer for imaging the kidney and monitoring renal tubular function. The radioactive isotope used in our studies is technetium 99m which is widely available in the US, all developed countries and is available in the major cities of most developing and many third world nations. Our secondary objective is to enhance the understanding of technetium chemistry and technetium radiopharmaceutical development so that the basic technetium research in this project will facilitate the development by others of new non-renal diagnostic technetium imaging tracers as well as rhenium radiopharmaceuticals which have an identical chemistry to technetium but which can be used for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK038842-24
Application #
8287197
Study Section
Special Emphasis Panel (ZRG1-MEDI-A (09))
Program Officer
Moxey-Mims, Marva M
Project Start
1986-09-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
24
Fiscal Year
2012
Total Cost
$340,110
Indirect Cost
$120,684
Name
Emory University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Lipowska, Malgorzata; Klenc, Jeffrey; Folks, Russell D et al. (2014) Initial Evaluation of (99m)Tc(CO)3(ASMA) as a Renal Tracer in Healthy Human Volunteers. Nucl Med Mol Imaging 48:216-24
Taylor, Andrew T (2014) Radionuclides in nephrourology, Part 2: pitfalls and diagnostic applications. J Nucl Med 55:786-98
Lipowska, Malgorzata; Klenc, Jeffrey; Shetty, Dinesh et al. (2014) Al18F-NODA-butyric acid: biological evaluation of a new PET renal radiotracer. Nucl Med Biol 41:248-53
Taylor, Andrew T (2014) Radionuclides in nephrourology, part 1: Radiopharmaceuticals, quality control, and quantitative indices. J Nucl Med 55:608-15
Perera, Theshini; Abhayawardhana, Pramuditha; Marzilli, Patricia A et al. (2013) Formation of a metal-to-nitrogen bond of normal length by a neutral sufonamide group within a tridentate ligand. A new approach to radiopharmaceutical bioconjugation. Inorg Chem 52:2412-21
Lipowska, Malgorzata; He, Haiyang; Xu, Xiaolong et al. (2010) Coordination modes of multidentate ligands in fac-[Re(CO)(3)(polyaminocarboxylate)] analogues of (99m)Tc radiopharmaceuticals. dependence on aqueous solution reaction conditions. Inorg Chem 49:3141-51
Perera, Theshini; Marzilli, Patricia A; Fronczek, Frank R et al. (2010) Several novel N-donor tridentate ligands formed in chemical studies of new fac-Re(CO)3 complexes relevant to fac-99mTc(CO)3 radiopharmaceuticals: attack of a terminal amine on coordinated acetonitrile. Inorg Chem 49:2123-31
Taylor, Andrew T; Lipowska, Malgorzata; Marzilli, Luigi G (2010) (99m)Tc(CO)3(NTA): a (99m)Tc renal tracer with pharmacokinetic properties comparable to those of (131)I-OIH in healthy volunteers. J Nucl Med 51:391-6
Perera, Theshini; Marzilli, Patricia A; Fronczek, Frank R et al. (2010) NH NMR shifts of new structurally characterized fac-[Re(CO)3(polyamine)]n+ complexes probed via outer-sphere hydrogen-bonding interactions to anions, including the paramagnetic [Re(IV)Br6]2- anion. Inorg Chem 49:5560-72

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