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24.10.2018 | Research Article

[¹⁸F]FE-OTS964: a Small Molecule Targeting TOPK for In Vivo PET Imaging in a Glioblastoma Xenograft Model

verfasst von: Giacomo Pirovano, Sheryl Roberts, Christian Brand, Patrick L. Donabedian, Christian Mason, Paula Demétrio de Souza, Geoff S. Higgins, Thomas Reiner

Erschienen in: Molecular Imaging and Biology | Ausgabe 4/2019

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Abstract

Purpose

Lymphokine-activated killer T cell-originated protein kinase (TOPK) is a fairly new cancer biomarker with great potential for clinical applications. The labeling of a TOPK inhibitor with F-18 can be exploited for positron emission tomography (PET) imaging allowing more accurate patient identification, stratification, and disease monitoring.

Procedures

[¹⁸F]FE-OTS964 was produced starting from OTS964, a preclinical drug which specifically binds to TOPK, and using a two-step procedure with [¹⁸F]fluoroethyl p-toluenesulfonate as a prosthetic group. Tumors were generated in NSG mice by subcutaneous injection of U87 glioblastoma cells. Animals were injected with [¹⁸F]FE-OTS964 and PET imaging and ex vivo biodistribution analysis was carried out.

Results

[¹⁸F]FE-OTS964 was successfully synthesized and validated in vivo as a PET imaging agent. The labeling reaction led to 15.1 ± 7.5 % radiochemical yield, 99 % radiochemical purity, and high specific activity. Chemical identity of the radiotracer was confirmed by co-elution on an analytical HPLC with a cold-labeled standard. In vivo PET imaging and biodistribution analysis showed tumor uptake of 3.06 ± 0.30 %ID/cc, which was reduced in animals co-injected with excess blocking dose of OTS541 to 1.40 ± 0.42 %ID/cc.

Conclusions

[¹⁸F]FE-OTS964 is the first TOPK inhibitor for imaging purposes and may prove useful in the continued investigation of the pharmacology of TOPK inhibitors and the biology of TOPK in cancer patients.

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Titel: [18F]FE-OTS964: a Small Molecule Targeting TOPK for In Vivo PET Imaging in a Glioblastoma Xenograft Model
verfasst von: Giacomo Pirovano
Sheryl Roberts
Christian Brand
Patrick L. Donabedian
Christian Mason
Paula Demétrio de Souza
Geoff S. Higgins
Thomas Reiner
Publikationsdatum: 24.10.2018
Verlag: Springer International Publishing
Erschienen in: Molecular Imaging and Biology / Ausgabe 4/2019
Print ISSN: 1536-1632
Elektronische ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-018-1288-6

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[¹⁸F]FE-OTS964: a Small Molecule Targeting TOPK for In Vivo PET Imaging in a Glioblastoma Xenograft Model