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Shan L.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 Dec 06 [updated 2013 Jan 29].


99mTc-Gly-Gly-Cys-(Arg)3-bombesin(2-14)-NH2, abbreviated as 99mTc-BN-A, is an analog of the bombesin (BN) peptide, which was synthesized by Liolios et al. for imaging of tumors that express gastrin-releasing peptide receptors (GRPR) (1). BN is an amphibian neuropeptide consisting of 14 amino acids (pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) (2, 3). It shares an identical C-terminal region (-Trp-Ala-Val-Gly-His-Leu-Met-NH2) with gastrin-releasing peptide (GRP), which is responsible for receptor binding and signal transduction (4, 5). There are three mammalian BN receptors, and GRPR (BB2 or BRS2; 384 amino acids) is the only one that is well characterized. GRPR is a glycosylated, 7-transmembrane, G-protein–coupled receptor that, upon binding with its ligands, gives rise to a complex cascade of intracellular reactions. In the physiological state, GRPR is expressed at low levels in non-neuroendocrine tissues of the breast and pancreas, and in neuroendocrine cells of the brain, gastrointestinal tract, lung, and prostate (6). On the contrary, GRPR is overexpressed in various tumors, establishing itself as an optimal target for theranostics (7-10). To date, a large number of BN derivatives have been synthesized based on either truncated BN(6-14) or BN(7-14) or full-length BN(1-14) (4, 10, 11). The truncated BN analogs are generally more stable in vivo, but the full-length analogs offer more flexible labeling sites through the amino acids 1 to 6. For most BN analogs, the amino acids on position 13 (Leu) and 14 (Met) have been replaced by unnatural amino acids, and Lys has been placed on position 3 for attachment of radiolabels. Spacers and chelators have also been widely used for conjugation purposes and for favorable kinetics. In 2009, Fragogeorgi et al. reported two 99mTc-labeled BN derivatives with different hydrophilicities and overall charges (12). One BN derivative, 99mTc-N3S-BN(2-14), had a sequence of 99mTc(V)O-Gly-Gly-Cys-bombesin(2-14). Another BN derivative, 99mTc-BN-O or 99mTc-N3S-X-BN(2-14), had the same sequence, but a basic amino acid spacer (X = Orn-Orn-Orn) was introduced. Both agents utilize the Gly-Gly-Cys as a tripeptide N3S-type chelator for radiolabeling, but 99mTc-BN-O is more hydrophilic than 99mTc-N3S-BN(2-14). Comparative studies have shown that hydrophilicity and charge strongly affect the binding properties and biodistribution patterns of the agents, and 99mTc-BN-O is superior to 99mTc-N3S-BN(2-14) for use in imaging tumors. To understand whether presence of a positively charged and highly polar spacer is critical for body clearance, the same group of investigators recently developed the agent 99mTc-BN-A, which is a C-terminally amidated BN(2-14) analog with a positively charged, more polar natural spacer (Arg)3 than the spacer (Orn)3 (1). Liolios et al. investigated the in vitro and in vivo properties of 99mTc-BN-A and compared to the properties of 99mTc-BN-O (1). This chapter summarizes the comparative data obtained by Liolios et al. with 99mTc-BN-A and 99mTc-BN-O (1). The data obtained with 99mTc-N3S-BN(2-14) and 99mTc-BN-O by Fragogeorgi et al. can be reviewed in the chapter on 99mTc-N3S-X-BN(2-14) in MICAD.

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