Received for publication June 24, 2005.
Revised October 24, 2005.
Accepted for publication October 24, 2005.

NC100668, a new tracer for imaging of venous thromboembolism: Disposition and metabolism in rats

Abstract

The ^99mTc-complex of NC100668 is being evaluated for nuclear medical imaging of venous thromboembolism. NC100668 is a 13 amino acid peptide with a Tc-binding chelator (NC100194) linked to the C-terminal end. Following injection in rats of [Asn-U-¹⁴C]NC100668 (labelling 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 (labelling 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 most likely represents ¹⁴C-labelled Lys which is reabsorbed in the kidney tubules and incorporated into protein metabolism. Metabolite profiling by HPLC 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. LC-MS analyses of rat urine samples obtained after injection of non-labelled NC100668 confirmed the identity of 2 metabolites generated from the C-terminal end of the molecule; Gly-NC100194 was identified as the major of these and NC100194 as a minor metabolite present at approximately one-tenth the amount of Gly-NC100194. No other metabolites were identified.

Key words: drug clearance, drug development, drug disposition, HPLC, mass spectrometry, metabolite identification, pharmacokinetics

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