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The biodistribution of NC100668 and the effect of excess NC100668 on the biodistribution and kidney retention of Tc-99m-NC100668 in the rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology. (Ahlström)
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2007 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 34, no 3, 315-323 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: (99m)Tc-NC100668 is being developed to aid the diagnosis of thromboemboli. The purpose of this study was to investigate if the presence of excess NC100668 interferes with the biodistribution and blood clot uptake of (99m)Tc-NC100668. The secondary aim was to investigate the causes underlying the kidney retention of (99m)Tc-NC100668. METHODS: The uptake of a (14)C-labelled analogue of NC100668, as well as (99m)Tc-NC100668, into plasma (in vitro) and blood (in vivo) clots was determined. The biodistribution of (99m)Tc-NC100668 at a range of NC100668 doses was studied in normal Wistar rats and those bearing experimentally induced deep venous thrombosis. The biodistribution of a negative control peptide and (99m)Tc-NC100668 plus L-lysine was studied in healthy male Wistar rats. RESULTS: The biodistribution as well as plasma clot uptake of [Asn-U-(14)C]NC100668 and (99m)Tc-NC100668 was similar. Apart from some reduction in kidney retention, the biodistribution and uptake of radioactivity into the blood clot were not significantly affected by the presence of up to 1000 times the clinical dose of NC100668. Kidney retention of radioactivity could be more effectively reduced by coadministration of 889 microg/kg NC100668 than 450 mg/kg L-lysine. A negative control peptide with no affinity for FXIIIa demonstrated very little kidney retention. CONCLUSIONS: The biodistribution and blood clot uptake of (99m)Tc-NC100668 and [Asn-U-(14)C]NC100668 are similar. With the exception of the kidneys, (99m)Tc-NC100668 biodistribution and blood clot uptake are unaffected by the presence of unlabelled NC100668. The kidney retention of radioactivity is probably due to transglutaminase activity and, to a lesser extent, nonspecific charge-mediated endocytosis.

Place, publisher, year, edition, pages
2007. Vol. 34, no 3, 315-323 p.
Keyword [en]
99mTc-NC100668, Biodistribution, Ligand dose, Thrombus, Rat
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-95166DOI: 10.1016/j.nucmedbio.2007.01.008ISI: 000245513800011PubMedID: 17383581OAI: oai:DiVA.org:uu-95166DiVA: diva2:169274
Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2012-03-06Bibliographically approved
In thesis
1. Pre-Clinical Evaluation of a Novel Radiotracer for the Diagnosis of DVT and Pulmonary Embolism.
Open this publication in new window or tab >>Pre-Clinical Evaluation of a Novel Radiotracer for the Diagnosis of DVT and Pulmonary Embolism.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are different aspects of a single condition, venous thrombo-embolic disease (VTE), a major cause of morbidity and mortality in the western world. Rapid diagnosis is critical, as timely medical intervention can have a substantial beneficial effect on the mortality rate.

Irrespective of its presentation, VTE is a difficult disease to diagnose. Pathologies unrelated to VTE can give rise to a clinical presentation similar to DVT or PE, resulting in a false positive diagnosis. This raises the risk of a patient being treated inappropriately. Therefore, there is a need for an agent that has high specificity and sensitivity for the detection of active blood clots, which are amenable to treatment by anticoagulant and/or thrombolytic therapy.

This work describes the pre-clinical efficacy studies performed on one such agent, 99mTc-NC100668. 99mTc-NC100668 is a substrate for factor XIIIa and as a potential physiological, rather than anatomical, marker of VTE it is hoped it will not give rise to the false negative and positive diagnoses that are inherent in the currently available diagnostic techniques, such as the ventilation perfusion (V/Q) scan, multidetector computer tomography or ultrasound.

It is reported in this work that 99mTc-NC100668 uptake and retention in blood clot was rapid and maintained over at least a 4 hour period in a rat model of DVT. Anticoagulant and thrombolytic therapies commonly used to treat thrombosis did not seriously impair the ability of 99mTc-NC100668 to detect thrombi. No significant tissue retention, which could interfere with the ability to image thrombi in vivo, was observed. Biodistribution and plasma clot uptake studies showed that 99mTc complex of gly-NC100194, the major metabolite of 99mTc-NC100668, would be unlikely to affect adversely the clinical utility of the test substance.

The in vitro uptake of 99mTc-NC100668 into forming plasma clots indicated that retention into human blood clots would be comparable with the observations made in the rat preclinical models.

The uptake of 99mTc-NC100668 in vitro and in vivo was much greater than could be accounted for by physical entrapment into the forming blood clots. The reduced uptake of a biologically inactive analogue of 99mTc-NC100668 both in vitro and in vivo indicated that the blood clot uptake and retention of 99mTc-NC100668 was mediated by factor XIIIa.

In conclusion, 99mTc-NC100668 might be useful in the detection of thrombo embolism.

Place, publisher, year, edition, pages
Uppsala: Institutionen för onkologi, radiologi och klinisk immunologi, 2006. 54 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 203
Radiology, Radiologisk forskning
urn:nbn:se:uu:diva-7321 (URN)91-554-6726-1 (ISBN)
Public defence
2006-12-08, Föreläsningssalen, Röntgen, Ing. 70, 1 tr, Akademiska sjukhuset, UPPSALA, 13:15
Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2011-05-19Bibliographically approved

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