Development and radiosynthesis of the first 18F-labeled inhibitor of monocarboxylate transporters (MCTs)

Masoud Sadeghzadeh; Rareş Petru Moldovan; Steffen Fischer; Barbara Wenzel; Friedrich Alexander Ludwig; Rodrigo Teodoro; Winnie Deuther-Conrad; Shirisha Jonnalagadda; Sravan K. Jonnalagadda; Emilis Gudelis; Algirdas Šačkus; Kei Higuchi; Vadivel Ganapathy; Venkatram R Mereddy; Lester R Drewes; Peter Brust

doi:10.1002/jlcr.3739

Development and radiosynthesis of the first ¹⁸F-labeled inhibitor of monocarboxylate transporters (MCTs)

Masoud Sadeghzadeh, Rareş Petru Moldovan, Steffen Fischer, Barbara Wenzel, Friedrich Alexander Ludwig, Rodrigo Teodoro, Winnie Deuther-Conrad, Shirisha Jonnalagadda, Sravan K. Jonnalagadda, Emilis Gudelis, Algirdas Šačkus, Kei Higuchi, Vadivel Ganapathy, Venkatram R Mereddy, Lester R Drewes, Peter Brust

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT-mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [¹⁸F]FACH ((E)-2-cyano-3-{4-[(3-[¹⁸F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α-cyano-4-hydroxycinnamic acid (FACH) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L-[¹⁴C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[¹⁸F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[¹⁸F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[¹⁸F]F-K_2.2.2-carbonate or [¹⁸F]TBAF. The final deprotected product [¹⁸F]FACH was only obtained when [¹⁸F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [¹⁸F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).

Original language	English (US)
Pages (from-to)	411-424
Number of pages	14
Journal	Journal of Labelled Compounds and Radiopharmaceuticals
Volume	62
Issue number	8
DOIs	https://doi.org/10.1002/jlcr.3739
State	Published - Jun 30 2019

Bibliographical note

Funding Information:
The Alexander von Humboldt Foundation and the University of Minnesota Duluth are acknowledged for financial supports. We are thankful to Dr. Karsten Franke for providing [18F]fluoride as well as Dr. Matthias Scheunemann for his scientific supports. We also thank the staff of the Institute of Analytical Chemistry, Department of Chemistry and Mineralogy of the University of Leipzig, for recording and processing the NMR and HR‐ MS spectra.

Funding Information:
The Alexander von Humboldt Foundation and the University of Minnesota Duluth are acknowledged for financial supports. We are thankful to Dr. Karsten Franke for providing [18F]fluoride as well as Dr. Matthias Scheunemann for his scientific supports. We also thank the staff of the Institute of Analytical Chemistry, Department of Chemistry and Mineralogy of the University of Leipzig, for recording and processing the NMR and HR-MS spectra.

Publisher Copyright:
© 2019 John Wiley & Sons, Ltd.

Keywords

[F]FACH
monocarboxylate transporters (MCTs)
positron emission tomography (PET)
radiofluorination
α-cyano-4-hydroxycinnamic acid (α-CHC)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1002/jlcr.3739

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Sadeghzadeh, M., Moldovan, R. P., Fischer, S., Wenzel, B., Ludwig, F. A., Teodoro, R., Deuther-Conrad, W., Jonnalagadda, S., Jonnalagadda, S. K., Gudelis, E., Šačkus, A., Higuchi, K., Ganapathy, V., Mereddy, V. R., Drewes, L. R., & Brust, P. (2019). Development and radiosynthesis of the first ¹⁸F-labeled inhibitor of monocarboxylate transporters (MCTs). Journal of Labelled Compounds and Radiopharmaceuticals, 62(8), 411-424. https://doi.org/10.1002/jlcr.3739

Sadeghzadeh, M, Moldovan, RP, Fischer, S, Wenzel, B, Ludwig, FA, Teodoro, R, Deuther-Conrad, W, Jonnalagadda, S, Jonnalagadda, SK, Gudelis, E, Šačkus, A, Higuchi, K, Ganapathy, V, Mereddy, VR , Drewes, LR & Brust, P 2019, 'Development and radiosynthesis of the first ¹⁸F-labeled inhibitor of monocarboxylate transporters (MCTs)', Journal of Labelled Compounds and Radiopharmaceuticals, vol. 62, no. 8, pp. 411-424. https://doi.org/10.1002/jlcr.3739

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abstract = "Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT-mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [18F]FACH ((E)-2-cyano-3-{4-[(3-[18F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α-cyano-4-hydroxycinnamic acid (FACH) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L-[14C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[18F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[18F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[18F]F-K2.2.2-carbonate or [18F]TBAF. The final deprotected product [18F]FACH was only obtained when [18F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [18F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).",

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note = "Funding Information: The Alexander von Humboldt Foundation and the University of Minnesota Duluth are acknowledged for financial supports. We are thankful to Dr. Karsten Franke for providing [18F]fluoride as well as Dr. Matthias Scheunemann for his scientific supports. We also thank the staff of the Institute of Analytical Chemistry, Department of Chemistry and Mineralogy of the University of Leipzig, for recording and processing the NMR and HR‐ MS spectra. Funding Information: The Alexander von Humboldt Foundation and the University of Minnesota Duluth are acknowledged for financial supports. We are thankful to Dr. Karsten Franke for providing [18F]fluoride as well as Dr. Matthias Scheunemann for his scientific supports. We also thank the staff of the Institute of Analytical Chemistry, Department of Chemistry and Mineralogy of the University of Leipzig, for recording and processing the NMR and HR-MS spectra. Publisher Copyright: {\textcopyright} 2019 John Wiley & Sons, Ltd.",

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doi = "10.1002/jlcr.3739",

language = "English (US)",

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T1 - Development and radiosynthesis of the first 18F-labeled inhibitor of monocarboxylate transporters (MCTs)

AU - Sadeghzadeh, Masoud

AU - Moldovan, Rareş Petru

AU - Fischer, Steffen

AU - Wenzel, Barbara

AU - Ludwig, Friedrich Alexander

AU - Teodoro, Rodrigo

AU - Deuther-Conrad, Winnie

AU - Jonnalagadda, Shirisha

AU - Jonnalagadda, Sravan K.

AU - Gudelis, Emilis

AU - Šačkus, Algirdas

AU - Higuchi, Kei

AU - Ganapathy, Vadivel

AU - Mereddy, Venkatram R

AU - Drewes, Lester R

AU - Brust, Peter

N1 - Funding Information: The Alexander von Humboldt Foundation and the University of Minnesota Duluth are acknowledged for financial supports. We are thankful to Dr. Karsten Franke for providing [18F]fluoride as well as Dr. Matthias Scheunemann for his scientific supports. We also thank the staff of the Institute of Analytical Chemistry, Department of Chemistry and Mineralogy of the University of Leipzig, for recording and processing the NMR and HR‐ MS spectra. Funding Information: The Alexander von Humboldt Foundation and the University of Minnesota Duluth are acknowledged for financial supports. We are thankful to Dr. Karsten Franke for providing [18F]fluoride as well as Dr. Matthias Scheunemann for his scientific supports. We also thank the staff of the Institute of Analytical Chemistry, Department of Chemistry and Mineralogy of the University of Leipzig, for recording and processing the NMR and HR-MS spectra. Publisher Copyright: © 2019 John Wiley & Sons, Ltd.

PY - 2019/6/30

Y1 - 2019/6/30

N2 - Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT-mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [18F]FACH ((E)-2-cyano-3-{4-[(3-[18F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α-cyano-4-hydroxycinnamic acid (FACH) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L-[14C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[18F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[18F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[18F]F-K2.2.2-carbonate or [18F]TBAF. The final deprotected product [18F]FACH was only obtained when [18F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [18F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).

AB - Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT-mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [18F]FACH ((E)-2-cyano-3-{4-[(3-[18F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α-cyano-4-hydroxycinnamic acid (FACH) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L-[14C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[18F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[18F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[18F]F-K2.2.2-carbonate or [18F]TBAF. The final deprotected product [18F]FACH was only obtained when [18F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [18F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).

KW - [F]FACH

KW - monocarboxylate transporters (MCTs)

KW - positron emission tomography (PET)

KW - radiofluorination

KW - α-cyano-4-hydroxycinnamic acid (α-CHC)

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