Automated radiochemical synthesis of [18F]FBEM: A thiol reactive synthon for radiofluorination of peptides and proteins

Kiesewetter, Dale O.; Jacobson, Orit; Lang, Lixin; Chen, Xiaoyuan

doi:10.1016/j.apradiso.2010.09.023

Cited by 47 publications

(63 citation statements)

References 13 publications

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“…Degassed phosphate-buffered saline (90 μL) and CH 3 CN were added to achieve a homogeneous solution. Then a solution of FBEM (82 μg (313 nmol)/50 μL) was added 15 . The resulting solution was incubated for 60 min at room temperature, diluted with 100 μL 0.1% TFA, and submitted to HPLC purification using the gradient described in the general experimental section.…”

Section: Methodsmentioning

confidence: 99%

PET of Insulinoma Using ¹⁸F-FBEM-EM3106B, a New GLP-1 Analogue

et al. 2011

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Derived from endocrine pancreatic beta cells, insulinomas express glucagon-like peptide-1 (GLP-1) receptor with high density and incidence. In this study, we labeled a novel GLP-1 analog, EM3106B, with 18F and performed PET imaging to visualize insulinoma tumors in an animal model. A GLP-1 analog that contains multiple lactam bridges, EM3106B, was labeled with 18F through a maleimide-based prosthetic group, N-2-(4-18F-fluorobenzamido) ethylmaleimide (18F-FBEM). The newly developed radiotracer was characterized by cell based receptor-binding assay, cell uptake and efflux assay. The stability in serum was evaluated by radio-HPLC analysis. In vivo PET imaging was performed in nude mice bearing subcutaneous INS-1 insulinoma tumors and MDA-MB-435 tumors of melanoma origin. Ex vivo biodistribution study was performed to confirm the PET imaging data. EM3106B showed high binding affinity (IC50 = 1.38 nM) and high cell uptake (5.25 ± 0.61% after 120 min incubation). 18F-FBEM conjugation of EM3106B resulted in high labeling yield (24.9 ± 2.4%) and high specific activity (>75 GBq/ μmol at the end of bombardment). EM3106B specifically bound and was internalized by GLP-1R positive INS-1 cells. After intravenous injection of 3.7 MBq (100 μCi) of 18F-FBEM-EM3106B, the INS-1 tumors were clearly visible with high contrast in relation to the contralateral background on PET images, and tumor uptake of 18F-FBEM-EM3106B was determined to be 28.5 ± 4.7 and 25.4 ± 4.1 %ID/g at 60 and 120 min, respectively. 18F-FBEM-EM3106B showed low uptake in MB-MDA-435 tumors with low level of GLP-1R expression. Direct tissue sampling biodistribution experiment confirmed high tracer uptake in INS-1 tumors and receptor specificity in both INS-1 tumor and pancreas. In conclusion, 18F-FBEM-EM3106B exhibited GLP-1R-receptor-specific targeting properties in insulinomas. The favorable characteristics of 18F-FBEM-EM3106B, such as high specific activity and high tumor uptake, and high tumor to non-target uptake, demonstrate that it is a promising tracer for clinical insulinoma imaging.

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Section: Methodsmentioning

confidence: 99%

PET of Insulinoma Using ¹⁸F-FBEM-EM3106B, a New GLP-1 Analogue

et al. 2011

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“…The desired amount of 18 F-FBEM (range, 388.5-984.2 MBq) was evaporated to near-dryness and mixed with 10 mL of ethanol (22), and 100-200 mg of Cys 40 -exendin-4 in 100 mL of 0.1% sodium ascorbate in phosphatebuffered saline (PBS) was added. The major radioactivity peak collected from the semipreparative high-performance liquid chromatography was the product.…”

Section: Radiochemical Synthesis Of 18 F-fbem-cys 40 -Exendin-4mentioning

confidence: 99%

PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

et al. 2012

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Glucagonlike peptide (GLP-1) and its receptor (GLP-1R) exhibit cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in both animal studies and clinical trials. However, the kinetics of GLP-1R expression in the infarcted/ischemic myocardium has not yet been explored. The purpose of this study was to monitor the presence and time course of regional myocardial GLP-1R expression after MI/R with noninvasive PET. Methods: Male Sprague-Dawley rats underwent a 45-min transient left coronary artery occlusion, followed by reperfusion. The myocardial infarction was confirmed by electrocardiogram and cardiac ultrasound. In vivo PET was performed to determine myocardial uptake of 18 F-FBEM-Cys 40 -exendin-4 at different time points after reperfusion. The localization of 18 F-FBEM-Cys 40 -exendin-4 accumulation was determined by coregistering 18 F-FDG PET and CT images. Ex vivo autoradiography, GLP-1R immunohistochemical staining, and Western blot analysis were performed to confirm the PET results. Results: Myocardial origin and infarcted/ischemic area localization of 18 F-FBEM-Cys 40 -exendin-4 accumulation was confirmed by coregistration of small-animal CT and 18 F-FDG images. At 8 h after MI/R, tracer uptake in the infarcted/ischemic region was 0.37 6 0.05 percentage injected dose per gram, significantly higher than that in the control group (P , 0.01). The localized tracer uptake decreased, relative to the 8-h time point, but was still significantly higher than the control group on days 1 and 3 after MI/R. At 2 wk after MI/R, the tracer uptake in the affected area showed no significant difference, compared with that in the healthy myocardium. Autoradiography showed the same trend of 18 F-FBEM-Cys 40 -exendin-4 uptake in the myocardial infarcted/ischemic area. The specificity of tracer uptake into ischemic myocardium was supported by decreased tracer uptake after the rats were pretreated with an excess amount of unlabeled exendin-4. Immunohistochemical staining and Western blotting of GLP-1R protein of excised cardiac sections confirmed that the change in uptake observed by PET corresponded to a change in GLP-1R expression. Conclusion: Noninvasive PET using 18 F-FBEM-Cys 40 -exendin-4 revealed a dynamic pattern of GLP-1R upregulation in the infarcted/ischemic area after MI/R. The imaging results will deepen our understanding of the mechanism of the cardioprotective effect of GLP-1 and its analogs and potentially provide guidance for optimization of the time frame of therapeutic intervention.

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“…Synthesis of N-[2-(4-[ 18 F]fluorobenzamido)ethyl]maleimide ([ 18 F]FBEM) was synthesized on the ELIXYS radiosynthesizer by straightforward adaptation of literature methods [30]. All tracers and prosthetic groups were purified using semi-preparative HPLC, and the collected fraction of each (suspended in its respective mobile phase; see Table 1) was used directly without further formulation.…”

Section: Methodsmentioning

confidence: 99%

Automatic concentration and reformulation of PET tracers via microfluidic membrane distillation

et al. 2017

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Short-lived radiolabeled tracers for positron emission tomography (PET) must be rapidly synthesized, purified, and formulated into injectable solution just prior to imaging. Current radiosynthesizers are generally designed for clinical use, and the HPLC purification and SPE formulation processes often result in a final volume that is too large for preclinical and emerging in vitro applications. Conventional technologies and techniques for reducing this volume tend to be slow, resulting in radioactive decay of the product, and often require manual handling of the radioactive materials. We present a fully-automated microfluidic system based on sweeping gas membrane distillation to rapidly perform the concentration and formulation process. After detailed characterization of the system, we demonstrate fast and efficient concentration and formulation of several PET tracers, evaluate residual solvent content to establish the safety of the formulated tracers for injection, and show that the formulated tracer can be used for in vivo imaging.

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Automated radiochemical synthesis of [18F]FBEM: A thiol reactive synthon for radiofluorination of peptides and proteins

Cited by 47 publications

References 13 publications

PET of Insulinoma Using ¹⁸F-FBEM-EM3106B, a New GLP-1 Analogue

PET of Insulinoma Using ¹⁸F-FBEM-EM3106B, a New GLP-1 Analogue

PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

Automatic concentration and reformulation of PET tracers via microfluidic membrane distillation

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Automated radiochemical synthesis of [18F]FBEM: A thiol reactive synthon for radiofluorination of peptides and proteins

Cited by 47 publications

References 13 publications

PET of Insulinoma Using 18F-FBEM-EM3106B, a New GLP-1 Analogue

PET of Insulinoma Using 18F-FBEM-EM3106B, a New GLP-1 Analogue

PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

Automatic concentration and reformulation of PET tracers via microfluidic membrane distillation

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Product

Resources

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PET of Insulinoma Using ¹⁸F-FBEM-EM3106B, a New GLP-1 Analogue

PET of Insulinoma Using ¹⁸F-FBEM-EM3106B, a New GLP-1 Analogue