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[18F]Fluorobenzoyl anti-HER2 Cys-diabody.


Shan L.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 Oct 31 [updated 2012 Nov 28].


[18F]Fluorobenzoyl (FB) anti-HER2 Cys-diabody (Cys-Db), abbreviated as [18F]FB-Cys-Db, was synthesized by Olafsen et al. for use in positron emission tomography (PET) of tumors expressing HER2 (1). Antibodies have long been considered to be the most attractive agents for molecular imaging because of their high specificity and binding affinity (2, 3). However, the usefulness of full antibodies as imaging agents is limited by their long circulation time in blood (several days to weeks), which requires a long time to optimally accumulate in tumors (1–2 days) (2). Because of their large molecular size (150 kDa), antibodies also exhibit poor tumor-penetrating ability, which leads to poor signal/noise ratio. To improve antibody pharmacokinetics without compromising the affinity and specificity, a promising solution is to reduce the antibody size or alter the Fc receptor-binding domain with protein engineering (2, 3). Indeed, various antibody fragments have been generated, such as single-chain variable fragment (scFv; 25–30 kDa), Fab (~50 kDa), and F(ab')2 (~110 kDa) fragments, bivalent scFv (tandem scFv and diabody, 50–60 kDa), and scFv-fusion proteins (80 kDa for minibody and 105 kDa for scFv-Fc) (2). These fragments exhibit good tumor penetration, fast clearance kinetics, high affinity, and high tumor/blood ratio, which are desirable for imaging agents. However, several issues with the use of antibody fragments as imaging agents remain to be solved, one of which is the diverse effects of labeling chemistry on the binding affinity of antibody fragments (4, 5). To reduce the diverse effects of labeling chemistry, various strategies have been designed. For example, Vaidyanathan and Zalutsky prepared 18F-labeled antibody fragments using N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB), which reacts with the ε-amino group of surface-exposed lysine residues on proteins (6). Labeling with this approach showed no loss of the antibody fragment affinity. Olafsen et al. further improved efficiency and speed of [18F]SFB production by adapting the synthesis to a three-step, one-pot, microwave-assisted method, followed by purification using either a single cartridge or high-performance liquid chromatography (HPLC) (1, 6). Alternatively, McCabe et al. first conjugated the diabody to DOTA, followed by 64Cu-radiolabeling through DOTA (7). All these strategies have been reported to be efficient and have fewer diverse effects on the binding affinity of antibody fragments. This chapter summarizes the data obtained with [18F]FB-Cys-Db. In another chapter, the data obtained with 64Cu-DOTA-CysDb are summarized.

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