13-18 May 2018
Casino Conference Centre
Europe/Prague timezone

Synthesis and radiofluorination of a novel monocarboxylate transporter 1 inhibitor for tumor imaging by PET

15 May 2018, 16:00
15m
Red Hall (Casino Conference Centre)

Red Hall

Casino Conference Centre

Reitenbergerova 4/95, Mariánské Lázně, Czech Republic
Verbal Radiopharmaceutical Chemistry, Labelled Compounds RPH 1

Speaker

Dr Masoud Sadeghzadeh (Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research site Leipzig)

Description

Monocarboxylate transporter 1 (MCT1) is an integral plasma membrane protein that bi-directionally transports lactate and ketone bodies and is highly expressed in non-hypoxic regions of human colon, brain, breast, lung and other tumors. Accordingly, MCT1 inhibitors are regarded to be of potential clinical use. In the current study we developed a new 18F-labeled radioligand for in vivo imaging of MCT1-overexpressing brain tumors by PET.
A new fluorinated analogue of α-cyano-4-hydroxycinnamic acid (RM231) was synthesized from m-anisidine via alkylation, ortho formylation and Knoevenagel condensation in 50% overall yield. Its MCT1 inhibition activity was evaluated via [14C]lactate uptake assay on rat brain endothelial 4 cells. The mesylated precursor was similarly prepared in 52% overall yield. Radiosynthesis of [18F]RM231 was achieved by a two-step reaction, starting with the radiofluorination using [18F]-K2CO3-K222 complex followed by protective group removal via hydrolysis under optimized reaction conditions.
RM231 showed relatively high MCT1 inhibition activity (IC50 = 12 nM). The radiolabeled intermediate was obtained by an optimized procedure (acetonitrile, 5.5 mg of K222, 0.7 mg of K2CO3, 12-15 GBq of K18F, 100 ̊C, 8 min) with 44-50% yield determined by radio-HPLC analysis (N=3, non-isolated). The final product was obtained by hydrolysis with TFA in dry dichloromethane at room temperature for 10 minutes with 29% yield (radio-HPLC, non-isolated).[18F]RM231 could be obtained after separation using semi-preparative HPLC (RP C18 column; 30% ACN, 20 mM NH4CO2H). Currently, attempts are made to stabilize and formulate the final product appropriately for biological investigation. The newly developed MCT1 radioligand is anticipated to be a useful agent for imaging of the tumors with PET. Accordingly, animal studies on the new radiotracer are currently under investigation.
Acknowledgement: This work was supported by the Alexander von Humboldt Foundation through postdoctoral fellowship for young researcher.

Primary author

Dr Masoud Sadeghzadeh (Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research site Leipzig)

Co-authors

Dr Rareş-Petru Moldovan (Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig) Dr Steffen Fischer (Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig) Dr Friedrich-Alexander Ludwig (Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig) Mrs Shirisha Gurrapu (Department of Biomedical Sciences, Medical School, University of Minnesota) Prof. Lester R. Drewes (Department of Biomedical Sciences, Medical School, University of Minnesota) Prof. Peter Brust (Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig)

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