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CtPyPyIm-(R)H2Nγ-PyImPyPy-C3-18F.

Authors

Zhang H.

Source

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2008 Nov 04 [updated 2008 Dec 01].

Excerpt

Polyamides (PAM) constructed from N-methylpyrrole (Py), N-methylimidazole (Im), 3-chlorothiophene (Ct), and N-methylhydroxypyrrole (Hp) amino acids comprise a class of synthetic oligomeric ligands that bind to the minor groove of DNA (1, 2). The aromatic heterocycles in the PAM orientate antiparallel with respect to the Watson-Crick base pair (bp), which leads to a specific recognition of DNA sequences (3). The recognition process follows a series of pairing rules; i.e., an ImPy specifies for G·C, a PyPy binds both A·T and T·A, an HpPy discriminates T·A over A·T, and a CtPy prefers T·A over A·T at the N-terminus. These aromatic amino acids can be programmed to a strand with more than two residues to recognize longer DNA sequences; for example, an ImPyPy motif specifies for the five-bp sequence 5’-WGWCW-3’ (W=A, T) instead of 5’-WGWWW-3’ (4). More complicated PAM motifs can be designed by adding small molecules such as β-alanine or γ-aminobutyric acid to covalently link between two antiparallel PAM strands, yielding substantial increases in affinities and specificities. For instance, an eight-ring hairpin motif, which has a γ-aminobutyric acid (γ-turn) linker to connect the carboxylic terminus of one polyamide to the amino terminus of another, exhibits ~100-fold higher affinity for binding a six-bp DNA sequence compared to the unlinked homodimers (4). PAM motifs are molecules that can permeate cell membranes and have been used in targeting a variety of DNA sequences in cell culture (5). The binding of PAM replaces the DNA-binding proteins and thus regulates the transcription of selected genes. The use of radiolabeled PAM aims at imaging gene regulations in vivo. Fluorine-18 [18F], with a half-life of 109.7 min and low β+-energy (0.64 MeV), represents the ideal radionuclide for position emission tomography (PET). The 18F-produced positron is annihilated with an electron, leading to the emission of two 511-keV photons ~180º apart, which is detected coincidentally with PET. Various peptides have been successively fluorinated with multistep 18F-acylation, using 18F-labeled prosthetic groups such as amino-reactive 18F-labeling agent N-succinimidyl 4-[18F]fluorobenzoate (6). To increase labeling efficiency, the fluorination also can be conducted via a two-step synthetic approach in which an oxime is formed between an aminooxy group in the peptide and an 18F-labeled aldehyde such as 4-[18F]fluorobenzaldehyde (6). CtPyPyIm-(R)H2Nγ-PyImPyPy-C3-18F ([18F]PIPAM8) is an 18F-labeled PAM used for PET that is obtained with the oxime ligation approach (5). [18F]PIPAM8 contains eight aromatic amino acids connected with a (R)-2,4-diaminobutyric acid, which is denoted as (R)H2N and is also known as an eight-ring hairpin motif. The use of chiral diaminobutyric acid as the γ-turn increases the overall binding affinity by 10-fold without reduction of sequence specificity (1). PIPAM8 is designed to bind specifically to the sequence 5’-ATACGT-3’ found in the vascular endothelial growth factor (VEGF) hypoxia response element (HRE) and can downregulate the hypoxia-induced VEGF expression in cell culture (7).

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