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Radiochemistry on electrodes: Synthesis of an 18F-labelled and in vivo stable COX-2 inhibitor.

ABSTRACT: New radiochemistry techniques can yield novel PET tracers for COX-2 and address the shortcomings in in vivo stability and specificity, which have held back clinical translation of tracers to image COX-2 expression. Current techniques limit radiosynthesis to analogs of the COX-2 inhibitors with fluorine-18 added via a carbon chain, or on an aromatic position which renders the radiolabeled analog less specific towards COX-2, resulting in tracers with low in vivo stability or specificity. To solve this problem, we have developed a new high affinity, 18F-labelled COX-2 inhibitor that is radiolabeled directly on a heteroaromatic ring. This molecule exhibits favorable biodistribution and increased metabolic stability. Synthesis of this molecule cannot be achieved by traditional means; consequently, we have developed an automated electrochemical radiosynthesis platform to synthesize up to 5 mCi of radiochemically pure 18F-COX-2ib in 4 hours (2% decay-corrected radiochemical yield). In vitro studies demonstrated clear correlation between COX-2 expression and uptake of the tracer. PET imaging of healthy animals confirmed that the molecule is excreted from blood within an hour, mainly through the hepatobiliary excretion pathway. In vivo metabolism data demonstrated that > 95% of the injected radioactivity remains in the form of the parent molecule 1 hour after injection.

SUBMITTER: Lebedev A

PROVIDER: S-EPMC5413030 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Radiochemistry on electrodes: Synthesis of an 18F-labelled and in vivo stable COX-2 inhibitor.

Lebedev Artem A Jiao Jing J Lee Jason J Yang Fan F Allison Nathanael N Herschman Harvey H Sadeghi Saman S

PloS one 20170502 5

New radiochemistry techniques can yield novel PET tracers for COX-2 and address the shortcomings in in vivo stability and specificity, which have held back clinical translation of tracers to image COX-2 expression. Current techniques limit radiosynthesis to analogs of the COX-2 inhibitors with fluorine-18 added via a carbon chain, or on an aromatic position which renders the radiolabeled analog less specific towards COX-2, resulting in tracers with low in vivo stability or specificity. To solve ...[more]

PMID: 28464017

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Project description:BACKGROUND:Targeted therapy of HER2 positive breast cancer has led to clinical success in some cases with primary and secondary resistance being major obstacles. Due to the substantial involvement of mTOR kinase in cell growth and proliferation pathways it is now targeted in combination treatments to counteract HER2 targeted therapy resistance. However, the selection of receptive patient populations for a specific drug combination is crucial. This work aims to develop a molecular probe capable of identifying patients with tumour populations which are receptive to RAD001 combination therapy. Based on the structure of a mTOR inhibitor specific for mTORC1, we designed, synthesised and characterised a novel benzofuran based molecular probe which suits late stage fluorination via Click chemistry. RESULTS:Synthesis of the alkyne precursor 5 proceeded in 27.5% yield over 7 linear steps. Click derivatisation gave the non-radioactive standard in 25% yield. Radiosynthesis of [18F]1-((1-(2-Fluoroethyl)-1H-1,2,3-triazol-4-yl) methyl)-4-((5-methoxy-2-phenylbenzofuran-4-yl) methyl) piperazine ([18F]mBPET-1) proceeded over two steps which were automated on an iPhase FlexLab synthesis module. In the first step, 2-[18F]fluoroethylazide ([18F]6) was produced, purified by automated distillation in 60% non-decay-corrected yield and subjected to Click conditions with 5. Semi-preparative RP-HPLC purification and reformulation gave [18F]mBPET-1 in 40%?±?5% (n?=?6) overall RCY with a process time of 90?min. Radiochemical purity was ?99% at end of synthesis (EOS) and???98% after 4?h at room temperature. Molar activities ranged from typically 24.8?GBq/?mol (EOS) to a maximum of 78.6?GBq/?mol (EOS). Lipophilicity of [18F]mBPET-1 was determined at pH?7.4 (logD7.4?=?0.89). [18F]mBPET-1 showed high metabolic stability when incubated with mouse S9 liver fractions which resulted in a 0.8% drop in radiochemical purity after 3?h. Cell uptake assays showed 1.3-1.9-fold increased uptake of the [18F]mBPET-1 in RAD001 sensitive compared to insensitive cells across a panel of 4 breast cancer cell lines. CONCLUSION:Molecular targeting of mTOR with [18F]mBPET-1 distinguishes mTOR inhibitor sensitive and insensitive cell lines. Future studies will explore the ability of [18F]mBPET-1 to predict response to mTOR inhibitor treatment in in vivo models.

Dataset Information

Radiochemistry on electrodes: Synthesis of an 18F-labelled and in vivo stable COX-2 inhibitor.

Publications

Radiochemistry on electrodes: Synthesis of an 18F-labelled and in vivo stable COX-2 inhibitor.

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