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A Thiol-Reactive ¹⁸F-Labeling Agent, N-[2-(4-¹⁸F-Fluorobenzamido)Ethyl]Maleimide, and Synthesis of RGD Peptide-Based Tracer for PET Imaging of _vß₃ Integrin Expression

Molecular Imaging Program at Stanford (MIPS) and Bio-X Program, Department of Radiology, Stanford University School of Medicine, Stanford, California

Correspondence: For correspondence or reprints contact: Xiaoyuan Chen, PhD, Molecular Imaging Program at Stanford (MIPS) and Bio-X Program, Department of Radiology, Stanford University School of Medicine, 1201 Welch Rd., Room P095, Stanford, CA 94305-5484. E-mail: shawchen{at}stanford.edu

The cell adhesion molecule integrin _vß₃ plays a key role in tumor angiogenesis and metastasis. A series of ¹⁸F-labeled RGD peptides have been developed for PET of integrin expression based on primary amine-reactive prosthetic groups. In this study we introduced a new method of labeling RGD peptides through a thiol-reactive synthon, N-[2-(4-¹⁸F-fluorobenzamido)ethyl]maleimide (¹⁸F-FBEM). Methods: ¹⁸F-FBEM was synthesized by coupling N-succinimidyl 4-¹⁸F-fluorobenzoate (¹⁸F-SFB) with N-(2-aminoethyl)maleimide. After high-pressure liquid chromatography purification, it was allowed to react with thiolated RGD peptides, and the resulting tracers were subjected to receptor-binding assay, in vivo metabolic stability assessment, biodistribution, and microPET studies in murine xenograft models. Results: Conjugation of monomeric and dimeric sulfhydryl-RGD peptides with ¹⁸F-FBEM was achieved in high yields (85% ± 5% nondecay-corrected on the basis of ¹⁸F-FBEM). The radiochemical purity of the ¹⁸F-labeled peptides was >98% and the specific activity was 100150 TBq/mmol. Noninvasive microPET and direct tissue sampling experiments demonstrated that both ¹⁸F-FBEM-SRGD (RGD monomer) and ¹⁸F-FBEM-SRGD2 (RGD dimer) had integrin-specific tumor uptake in subcutaneous U87MG glioma and orthotopic MDA-MB-435 breast cancer xenografts. Conclusion: The new tracer ¹⁸F-FBEM-SRGD2 was synthesized with high specific activity via ¹⁸F-FBEM and the tracer exhibited high receptor-binding affinity, tumor-targeting efficacy, metabolic stability, as well as favorable in vivo pharmacokinetics. The new synthon ¹⁸F-FBEM developed in this study will also be useful for radiolabeling of other thiolated biomolecules.

Key Words: thiol-reactive synthon • ¹⁸F-FBEM • microPET • ¹⁸F labeling • integrin _vß₃

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