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Nc100668, a new tracer for imaging of venous thromboembolism: disposition and metabolism in rats.

Abstract
The 99mTc-complex of NC100668 [Acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194] is being evaluated for nuclear medical imaging of venous thromboembolism. NC100668 is a 13-amino acid peptide with a Tc-binding chelator [NC100194; -NH-CH2-CH2-N(CH2-CH2-NH-C(CH3)2-C(CH3)=N-OH)2] linked to the C-terminal end. Following injection in rats of [Asn-U-14C]NC100668 (labeling of the N-terminal amino acid), approximately 70% of the radioactivity was recovered in urine within 3 days. Following injection of [Lys-U-14C]NC100668 (labeling close to the C-terminal amino acid), radioactivity was cleared more slowly, with only 8% recovered in urine and approximately 80% of the radioactivity present in the body after 3 days. The highest concentration of radioactivity in the body following injection of [Lys-U-14C]NC100668 was observed in the kidney inner cortex; this probably represents 14C-labeled Lys, which is reabsorbed in the kidney tubules and incorporated into protein metabolism. Metabolite profiling by high-performance liquid chromatography with radiochemical detection revealed that following injection of [Asn-U-14C]NC100668, there is a rapid appearance in blood of one peak containing radioactive metabolite(s) originating from the N-terminal part of the molecule. In urine samples, only this radioactive peak was observed with no intact NC100668 remaining; this very hydrophilic N-terminal metabolite was probably either the N-terminal amino acid or a very short peptide. Liquid chromatography-mass spectrometry analyses of rat urine samples obtained after injection of nonlabeled NC100668 confirmed the identity of two metabolites generated from the C-terminal end of the molecule; Gly-NC100194 was identified as the major of these metabolites and NC100194 as a minor metabolite present at approximately one-tenth the amount of Gly-NC100194. No other metabolites were identified.
AuthorsTore Skotland, Svein Olaf Hustvedt, Inger Oulie, Petter Balke Jacobsen, Grete Arneberg Friisk, Ann Svendsen Langøy, Steinar Uran, Jessie Sandosham, Alan Cuthbertson, Kim Gunnar Toft
JournalDrug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 34 Issue 1 Pg. 111-20 (Jan 2006) ISSN: 0090-9556 [Print] United States
PMID16251253 (Publication Type: Journal Article)
Chemical References
  • Peptide Fragments
  • Peptides
  • Radioactive Tracers
  • Radiopharmaceuticals
  • acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194
Topics
  • Amino Acid Sequence
  • Animals
  • Animals, Outbred Strains
  • Autoradiography
  • Chromatography, High Pressure Liquid (methods)
  • Drug Stability
  • Feces (chemistry)
  • Female
  • Gas Chromatography-Mass Spectrometry (methods)
  • Image Enhancement (methods)
  • Injections
  • Male
  • Peptide Fragments (metabolism, urine)
  • Peptides (chemical synthesis, metabolism, pharmacokinetics)
  • Protein Binding (drug effects)
  • Radioactive Tracers
  • Radiopharmaceuticals (chemical synthesis, metabolism, pharmacokinetics)
  • Rats
  • Thromboembolism (diagnosis, radionuclide imaging)
  • Tissue Distribution
  • Venous Thrombosis (diagnosis, radionuclide imaging)

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