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A New Highly Reactive and Low Lipophilicity Fluorine-18 Labeled Tetrazine Derivative for Pretargeted PET Imaging.

ABSTRACT: A new (18)F-labeled tetrazine derivative was developed aiming at optimal radiochemistry, fast reaction kinetics in inverse electron-demand Diels-Alder cycloaddition (IEDDA), and favorable pharmacokinetics for in vivo bioorthogonal chemistry. The radiolabeling of the tetrazine was achieved in high yield, purity, and specific activity under mild reaction conditions via conjugation with 5-[(18)F]fluoro-5-deoxyribose, providing a glycosylated tetrazine derivative with low lipophilicity. The (18)F-tetrazine showed fast reaction kinetics toward the most commonly used dienophiles in IEDDA reactions. It exhibited excellent chemical and enzymatic stability in mouse plasma and in phosphate-buffered saline (pH 7.41). Biodistribution in mice revealed favorable pharmacokinetics with major elimination via urinary excretion. The results indicate that the glycosylated (18)F-labeled tetrazine is an excellent candidate for in vivo bioorthogonal chemistry applications in pretargeted PET imaging approaches.

SUBMITTER: Keinanen O

PROVIDER: S-EPMC4716598 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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A New Highly Reactive and Low Lipophilicity Fluorine-18 Labeled Tetrazine Derivative for Pretargeted PET Imaging.

Keinänen Outi O Li Xiang-Guo XG Chenna Naveen K NK Lumen Dave D Ott Jennifer J Molthoff Carla F M CF Sarparanta Mirkka M Helariutta Kerttuli K Vuorinen Tapani T Windhorst Albert D AD Airaksinen Anu J AJ

ACS medicinal chemistry letters 20151210 1

A new (18)F-labeled tetrazine derivative was developed aiming at optimal radiochemistry, fast reaction kinetics in inverse electron-demand Diels-Alder cycloaddition (IEDDA), and favorable pharmacokinetics for in vivo bioorthogonal chemistry. The radiolabeling of the tetrazine was achieved in high yield, purity, and specific activity under mild reaction conditions via conjugation with 5-[(18)F]fluoro-5-deoxyribose, providing a glycosylated tetrazine derivative with low lipophilicity. The (18)F-te ...[more]

PMID: 26819667

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Project description:Background: The pretargeted imaging strategy using inverse electron demand Diels-Alder (IEDDA) cycloaddition between a trans-cyclooctene (TCO) and tetrazine (Tz) has emerged and rapidly grown as a promising concept to improve radionuclide imaging and therapy in oncology. This strategy has mostly relied on the use of radiolabeled Tz together with TCO-modified targeting vectors leading to a rapid growth of the number of available radiolabeled tetrazines, while only a few radiolabeled TCOs are currently reported. Here, we aim to develop novel and structurally diverse 18F-labeled cis-dioxolane-fused TCO (d-TCO) derivatives to further expand the bioorthogonal toolbox for in vivo ligation and evaluate their potential for positron emission tomography (PET) pretargeted imaging. Results: A small series of d-TCO derivatives were synthesized and tested for their reactivity against tetrazines, with all compounds showing fast reaction kinetics with tetrazines. A fluorescence-based pretargeted blocking study was developed to investigate the in vivo ligation of these compounds without labor-intensive prior radiochemical development. Two compounds showed excellent in vivo ligation results with blocking efficiencies of 95 and 97%. Two novel 18F-labeled d-TCO radiotracers were developed, from which [18F]MICA-214 showed good in vitro stability, favorable pharmacokinetics, and moderate in vivo stability. Micro-PET pretargeted imaging with [18F]MICA-214 in mice bearing LS174T tumors treated with tetrazine-modified CC49 monoclonal antibody (mAb) (CC49-Tz) showed significantly higher uptake in tumor tissue in the pretargeted group (CC49-Tz 2.16 ± 0.08% ID/mL) when compared to the control group with nonmodified mAb (CC49 1.34 ± 0.07% ID/mL). Conclusions: A diverse series of fast-reacting fluorinated d-TCOs were synthesized. A pretargeted blocking approach in tumor-bearing mice allowed the choice of a lead compound with fast reaction kinetics with Tz. A novel 18F-labeled d-TCO tracer was developed and used in a pretargeted PET imaging approach, allowing specific tumor visualization in a mouse model of colorectal cancer. Although further optimization of the radiotracer is needed to enhance the tumor-to-background ratios for pretargeted imaging, we anticipate that the 18F-labeled d-TCO will find use in studies where increased hydrophilicity and fast bioconjugation are required.

Dataset Information

A New Highly Reactive and Low Lipophilicity Fluorine-18 Labeled Tetrazine Derivative for Pretargeted PET Imaging.

Publications

A New Highly Reactive and Low Lipophilicity Fluorine-18 Labeled Tetrazine Derivative for Pretargeted PET Imaging.

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