Abstract
The C-X-C motif chemokine receptor 4 (CXCR4) is a seven-transmembrane G protein-coupled receptor that is overexpressed in numerous diseases, particularly in various cancers and is a powerful chemokine, attracting cells to the bone marrow niche. Therefore, CXCR4 is an attractive target for imaging and therapeutic purposes. The goal of this study is to develop an efficient, reproducible, and straightforward method to prepare a fluorine-18 labeled CXCR4 ligand. 6-[18F]Fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester (6-[18F]FPy-TFP) and nicotinic acid N-hydroxysuccinimide ester (6-[18F]SFPy) have been prepared using ‘fluorination on the Sep-Pak’ method. Conjugation of 6-[18F]SFPy or 6-[18F]FPy-TFP with the alpha-amino group at the N terminus of the protected T140 precursor followed by deprotection, yielded the final product 6-[18F]FPy-T140. The overall radiochemical yields were 6–17% (n = 15, decay-corrected) in a 90-min radiolabeling time with a radiochemical purity >99%. 6-[18F]FPy-T140 exhibited high specific binding and nanomolar affinity for CXCR4 in vitro, indicating that the biological activity of the peptide was preserved. For the first time, [18F]SFPy has been prepared using ‘fluorination on the Sep-Pak’ method that allows rapid automated synthesis of 6-[18F]FPy-T140. In addition to increased synthetic efficiency, this construct binds with CXCR4 in high affinity and may have potential as an in vivo positron emission tomography (PET) imaging agent. This radiosynthesis method should encourage wider use of this PET agent to quantify CXCR4 in both research and clinical settings.
Highlights
Chemokine receptors (CRs) are seven-transmembrane G protein-coupled receptors that trigger intracellular signaling and drive cell polarization, adhesion, and migration [1]
The structure of CXCR4 consists of 352 amino acid residues comprising an N-terminal domain, seven TM domains, three extracellular loops (ECL), three intracellular loops (ICL), and a C-terminal domain [6]
Siebeneicher et al first reported the synthesis of 6-[18 F]SFPy in a three-step
Summary
Chemokine receptors (CRs) are seven-transmembrane G protein-coupled receptors that trigger intracellular signaling and drive cell polarization, adhesion, and migration [1]. The chemokine receptor type 4 (CXCR4) is a distinctive member of the CR family, possessing additional functions during embryonic development, and has been widely studied with the initial discovery that CXCR4 is one of the co-receptors for human immunodeficiency virus (HIV) entry into target cells [2,3,4,5]. The structure of CXCR4 consists of 352 amino acid residues comprising an N-terminal domain, seven TM domains, three extracellular loops (ECL), three intracellular loops (ICL), and a C-terminal domain [6]. This chemokine receptor is overexpressed in a variety of cancers including kidney, lung, brain, prostate, breast, pancreas, ovarian, and melanomas [7,8,9]. The natural ligand for CXCR4, CXCL12, known as a stromal cell-derived
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