title: Monoanionic99mTc-tricarbonyl-aminopolycarboxylate complexes with uncharged pendant groups: Radiosynthesis and evaluation as potential renal tubular tracers.
abstract: BACKGROUND
  99mTc(CO)3-nitrilotriacetic acid,99mTc(CO)3(NTA), is a new renal tubular agent with pharmacokinetic properties comparable to those of131I-OIH but the clearance of99mTc(CO)3(NTA) and131I-OIH is still less than the clearance of PAH, the gold standard for the measurement of effective renal plasma flow. At physiological pH, dianionic99mTc(CO)3(NTA) has a mononegative inner metal-coordination sphere and a mononegative uncoordinated carboxyl group. To evaluate alternate synthetic approaches, we assessed the importance of an uncoordinated carboxyl group, long considered essential for tubular transport, by evaluating the pharmacokinetics of three analogs with the99mTc(CO)3(NTA) metal-coordination sphere but with uncharged pendant groups.
  
  
  METHODS
  99mTc(CO)3complexes with N-(2-acetamido)iminodiacetic acid (ADA), N-(2-hydroxyethyl)iminodiacetic acid (HDA) and N-(fluoroethyl)iminodiacetic acid (FEDA) were prepared using a tricarbonyl kit and isolated by HPLC. The pharmacokinetics were evaluated in Sprague-Dawley rats, with131I-OIH as an internal control; urine was analyzed for metabolites. Plasma protein binding and erythrocyte uptake were determined from the 10min blood samples. Re(CO)3(FEDA), the analog of99mTc(CO)3(FEDA), was prepared and characterized.
  
  
  RESULTS
  99mTc(CO)3(ADA),99mTc(CO)3(HDA) and99mTc(CO)3(FEDA) were efficiently prepared as a single species with high radiochemical purities (>99%). These new monoanionic99mTc(CO)3tracers with uncharged dangling groups all showed rapid blood clearance and high specificity for renal excretion. Activity in the urine, as a percent of131I-OIH at 10 and 60min, was 96% and 99% for ADA, 96% and 100% for HDA, and 100% and 99% for FEDA, respectively. Each new tracer was excreted unchanged in the urine. The Re(CO)3(FEDA) structure adds compelling evidence that such99mTc(CO)3(NTA) analogs have metal-coordination spheres identical to that of99mTc(CO)3(NTA).
  
  
  CONCLUSIONS
  New tracers lacking the negatively charged pendant carboxyl group previously thought to be essential for rapid renal extraction,99mTc(CO)3(ADA),99mTc(CO)3(HDA) and99mTc(CO)3(FEDA), exhibit pharmacokinetics in rats comparable to those of99mTc(CO)3(NTA) and131I-OIH. Furthermore, these encouraging results in rats warrant evaluation of this new tracer type in humans.
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA. Electronic address: mlipows@emory.edu.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Lipowska
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Klenc
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Nashwa
authors.initials: N
authors.lastname: Jarkas
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA, USA.
authors.forename: Luigi G
authors.initials: LG
authors.lastname: Marzilli
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001692:Biological Transport; D002264:Carboxylic Acids / Q000737:chemistry*; D004912:Erythrocytes / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D015609:Organotechnetium Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011849:Radioactive Tracers; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D002264:Carboxylic Acids; D015609:Organotechnetium Compounds; D011849:Radioactive Tracers