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99mTc-Labeled hydrazinonicotinamide-cysteine-annexin A5.


Chopra A.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2010 Jan 13 [updated 2010 Mar 04].


The complex process of programmed cell death (apoptosis) has a very important function in the normal development and differentiation of tissues in animals (1). An increased rate of apoptosis can result in diseases of the cardiovascular (e.g., stroke, myocardial infarction, etc.), nervous (e.g., neurodegeneration), or immune (e.g., autoimmunity) systems, and the development of cancer is often attributed to a reduced rate of apoptosis (2, 3). A characteristic feature of apoptosis is the exposure of phosphatidylserine (PS), a negatively charged phospholipid that is usually present on the inner layer of the cell membrane, due to the process of membrane inversion observed during cell death (4). Also, annexin A5 (a 36-kD protein) is known to bind specifically to the exposed PS on apoptotic cell membranes (5) and it has been conjugated to a variety of nuclides or fluorescent dyes for the detection and visualization of apoptosis in tissues with different disease pathologies using scintigraphic and optical techniques (6). 99mTechnetium-labeled hydrazinonicotinamide-annexin A5 (99mTc-HYNIC-annexin A5) is a commonly used probe for the imaging of apoptotic tissue with single-photon emission computed tomography (SPECT) (3). To generate 99mTc-HYNIC-annexin A5, the conjugation of HYNIC to annexin A5 is achieved by non-specifically directing HYNIC to an amino group on one of the 21 lysine residues in the protein structure, and any one of the lysine residues may bind the conjugating agent resulting in the formation of a molecule with an uncertain structure. In an effort to develop an annexin A5–based apoptosis imaging agent with a clear chemical structure, Fonge et al., using site-directed mutagenesis, incorporated a cysteine residue on the concave side of the protein to avoid altering the PS binding site on the convex side of the molecule (7) (for structural information of annexin, see van Genderen et al. (7)) and used the modified protein (cys-annexin A5) to generate HYNIC-cys-annexin A5 (3). HYNIC-cys-annexin A5 was subsequently labeled with 99mTc (99mTc-HYNIC-cys-annexin A5), and the biodistribution of this radiochemical was investigated in normal mice and compared to the biodistribution of 99mTc-HYNIC-annexin A5 in another group of the same animals (3). 99mTc-HYNIC-cys-annexin A5 uptake by the liver of mice treated with anti-Fas monoclonal antibody (anti-Fas mAb) was shown to detect the induced hepatic apoptosis in the animals. In another study, myocardial infarction in rabbits was visualized with 99mTc-HYNIC-cys-annexin A5 using SPECT.

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