PT  - JOURNAL ARTICLE
AU  - David Edwards
AU  - Mark Battle
AU  - Rochelle Lear
AU  - Gill Farrar
AU  - D. Jon Barnett
AU  - Vanessa Godden
AU  - Catherine Coombes
AU  - Alexandra Oliveira
AU  - Håkan Ahlström
TI  - THE IN VIVO AND IN VITRO METABOLIC PROFILE OF <sup>99M</sup>TC-NC100668, A NEW TRACER FOR IMAGING VENOUS THROMBOEMBOLISM: IDENTIFICATION AND BIODISTRIBUTION OF THE PRINCIPAL RADIOLABELED METABOLITE
AID  - 10.1124/dmd.106.009696
DP  - 2006 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 1128--1135
VI  - 34
IP  - 7
4099  - http://dmd.aspetjournals.org/content/34/7/1128.short
4100  - http://dmd.aspetjournals.org/content/34/7/1128.full
SO  - Drug Metab Dispos2006 Jul 01; 34
AB  - 99mTc-NC100668 [Acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194] is a radiopharmaceutical imaging agent being developed to aid the diagnosis of thromboembolism. The stability profile of 99mTc-NC100668 was investigated by high-performance liquid chromatography (HPLC) after in vitro exposure to blood and plasma obtained from rat and human, as well as to urine and bile obtained from rat. The metabolic profile of 99mTc-NC100668 exposed to human and rat hepatic S9 (a liver homogenate-rich cytochrome P450) was also studied. The profile of 99mTc-labeled species in plasma, urine, and bile was investigated following i.v. administration of 99mTc-NC100668 to rat. The major species observed in vitro and in vivo consisted of the 99mTc-chelator (NC100194) [N,N-Bis(N-(1,1-dimethyl-2-(hydroxylimino-)propyl)aminoethyl)aminoethylamine] attached to the C-terminal amino acid residue and referred to as 99mTc-complex of Gly-NC100194. The identity of the major metabolite was confirmed by cochromatography with an authentic standard and the genuine metabolite using a second HPLC method. The minor metabolites were sodium pertechnetate (99mTc) and 99mTc-NC100194. In addition, a small number of other species were transiently observed in vitro; they were not investigated further. The biodistribution of the major metabolite was studied in male Wistar rats. The affinity of the major metabolite toward plasma clot was established using a plasma clot-forming assay. A minor uptake of 99mTc-complex of Gly-NC100194 in the plasma clot and a rapid removal from the body were noted. In conclusion, the metabolites of 99mTc-NC100668 are not anticipated to have a negative impact on the ability of the test substance to image blood clots. The American Society for Pharmacology and Experimental Therapeutics