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Eur J Med Chem. 2018 Sep 5;157:437-446. doi: 10.1016/j.ejmech.2018.08.014. Epub 2018 Aug 6.

99mTc(CO)3+ labeled domain I/II-specific anti-EGFR (scFv)2 antibody fragment for imaging EGFR expression.

Author information

1
Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon, SK, Canada; Saskatchewan Centre for Cyclotron Sciences (SCCS), The Fedoruk Centre, Saskatoon, SK, Canada.
2
Department of Pathology and Laboratory Medicine, University of Saskatchewan, College of Medicine, Saskatoon, SK, Canada.
3
Department of Pathology and Laboratory Medicine, University of Saskatchewan, College of Medicine, Saskatoon, SK, Canada. Electronic address: ron.geyer@usask.ca.
4
Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon, SK, Canada; Saskatchewan Centre for Cyclotron Sciences (SCCS), The Fedoruk Centre, Saskatoon, SK, Canada; Department of Medical Imaging, Royal University Hospital Saskatoon, Saskatoon, SK, Canada. Electronic address: humphrey.fonge@usask.ca.

Abstract

Bifunctional chelators (BFCs) are covalently linked to biologically active targeting molecules and radiolabeled with radiometals. Technetium-99 m (99mTc) is the most widely used isotope in nuclear medicine because of its excellent physical properties. The objective of this study was to synthesize and characterize a novel BFC that allows for the labeling of antibodies and antibody fragments using the 99mTc(CO)3+ core which forms a very stable complex with 99mTc in the +1 oxidation sate. This study reports the synthesis of a BFC 1-pyrrolidinyl-2,5-dione-11-(bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino)undecanoic acid (SAAC-CIM NHS ester), and the in vitro and in vivo evaluation of 99mTc(CO)3-SAAC-CIM-DLO6-(scFv)2 (99mTc(CO)3-DLO6-(scFv)2), a domain I/II-specific anti-epidermal growth factor receptor I (anti-EGFR) antibody fragment. The chelator allowed radiolabeling the (scFv)2 antibody fragment in very mild conditions with no significant decrease in binding to EGFR. Radiochemical yields of >50% (radiochemical purity > 95%) of the resulting anti-EGFR (scFv)2 immunoconjugate 99mTc(CO)3-DLO6-(scFv)2 was obtained. The radioimmunoconjugate was stable in histidine challenge experiments with less than 20% transchelation at 24 h after challenge in the presence of a 1500-fold excess of histidine. In vivo biodistribution of 99mTc(CO)3-DLO6-(scFv)2 indicates that the tracer was mainly cleared via renal excretion and to a lesser extent via the hepatobiliary pathway. The microSPECT imaging studies performed in mice confirmed the in vitro affinity results. The 99mTc(CO)3-DLO6-(scFv)2 shows some promising properties and warrants further investigation for imaging EGFR.

KEYWORDS:

(99m)Tc-tricarbonyl; Domain-specific imaging agent; EGFR; SPECT imaging

PMID:
30103192
DOI:
10.1016/j.ejmech.2018.08.014
[Indexed for MEDLINE]

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