Nc100668, a new tracer for imaging of venous thromboembolism: disposition and metabolism in rats.
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.
Skotland
Tore
T
Research and Development, GE Healthcare Bio-Sciences, Nycoveien 2, N-0401 Oslo, Norway. tore.skotland@ge.com
Hustvedt
Svein Olaf
SO
Oulie
Inger
I
Jacobsen
Petter Balke
PB
Friisk
Grete Arneberg
GA
Langøy
Ann Svendsen
AS
Uran
Steinar
S
Sandosham
Jessie
J
Cuthbertson
Alan
A
Toft
Kim Gunnar
KG
D000595:Amino Acid Sequence; D000818:Animals; D021461:Animals, Outbred Strains; D001345:Autoradiography; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004355:Drug Stability; D005243:Feces / Q000737:chemistry; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D007089:Image Enhancement / Q000379:methods; D007267:Injections; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism / Q000652:urine; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D011485:Protein Binding / Q000187:drug effects; D011849:Radioactive Tracers; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D013923:Thromboembolism / Q000175:diagnosis / Q000000981:diagnostic imaging; D014018:Tissue Distribution; D020246:Venous Thrombosis / Q000175:diagnosis / Q000000981:diagnostic imaging
D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D010455:Peptides; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; C507860:acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194