A thiol-reactive 18F-labeling agent, N-[2-(4-18F-fluorobenzamido)ethyl]maleimide, and synthesis of RGD peptide-based tracer for PET imaging of alpha v beta 3 integrin expression.

Abstract

UNLABELLED:

The cell adhesion molecule integrin alpha v beta 3 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 100 approximately 150 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.

• Authors: Weibo Cai, Xianzhong Zhang, Yun Wu, Xiaoyuan Chen
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 47 Issue 7 Pg. 1172-80 (Jul 2006) ISSN: 0161-5505 [Print] United States
• PMID: 16818952 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Fluorine Radioisotopes
• Integrin alphaVbeta3
• Maleimides
• N-(2-(4-18F-fluorobenzamido)ethyl)maleimide
• Oligopeptides
• Radiopharmaceuticals
• Sulfhydryl Compounds
• maleimide
• arginyl-glycyl-aspartic acid

Topics

• Animals
• Cell Line, Tumor
• Fluorine Radioisotopes (pharmacology)
• Humans
• Integrin alphaVbeta3 (biosynthesis, chemistry)
• Maleimides (pharmacology)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Oligopeptides (chemistry)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (pharmacology)
• Sulfhydryl Compounds (chemistry)