PT  - JOURNAL ARTICLE
AU  - Tore Skotland
AU  - Svein Olaf Hustvedt
AU  - Inger Oulie
AU  - Petter Balke Jacobsen
AU  - Grete Arneberg Friisk
AU  - Ann Svendsen Langøy
AU  - Steinar Uran
AU  - Jessie Sandosham
AU  - Alan Cuthbertson
AU  - Kim Gunnar Toft
TI  - NC100668, A NEW TRACER FOR IMAGING OF VENOUS THROMBOEMBOLISM: DISPOSITION AND METABOLISM IN RATS
AID  - 10.1124/dmd.105.006239
DP  - 2006 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 111--120
VI  - 34
IP  - 1
4099  - http://dmd.aspetjournals.org/content/34/1/111.short
4100  - http://dmd.aspetjournals.org/content/34/1/111.full
SO  - Drug Metab Dispos2006 Jan 01; 34
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics