Synthesis and evaluation of a radiometal-labeled macrocyclic chelator-derivatised thymidine analog

Nuclear Medicine and Biology
Michaela SchmidSven N Reske

Abstract

Several radiolabeled thymidine analogs as metabolic probes of cell proliferation were developed specifically addressing DNA synthesis. Thymidine analogs containing carboranylalkyl groups for neutron capture therapy at the N-3 position were found to be good substrates for cytosolic thymidine kinase 1 (TK1). According to this approach, a DO3A macrocycle in N-3 position was attached to thymidine. The 3-DO3A thymidine analog was labeled with 68Ga and 111In. Different lipophilicities of the corresponding radiometal-thymidines were detected via RP-HPLC. [111In]DO3A-thymidine ([111In]D3T) was evaluated for cellular uptake in different cell lines (HL60 and DoHH2). Cellular uptake was low in both cell lines. Phosphorylation of the radioconjugates by TK1 was negligible. Although stable complexation of radiometals to thymidine was obtained, introduction of the macrocycle DO3A reduced the affinity to cytosolic TK1 drastically. Low cellular uptake can be ascribed to missing substrate specificity of [111In]DO3A-thymidine for TK1. The absence of substrate specificity may be due to the bulky macrocyclic chelator and partial charges remaining on the coordination sphere due to a more complex solution structure.

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Citations

Apr 27, 2013·Future Medicinal Chemistry·Ahmed KhalilWerner Tjarks
Nov 14, 2008·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Raquel GarciaIsabel Santos
Apr 23, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xiaojiang DuanJunbo Zhang
Jun 10, 2017·Cancer Biotherapy & Radiopharmaceuticals·Jun Young LeeSang Wook Kim
Dec 1, 2007·Chemical Communications : Chem Comm·Werner TjarksRolf F Barth
Aug 28, 2014·Beilstein Journal of Organic Chemistry·Mariola Koszytkowska-Stawińska, Włodzimierz Buchowicz
Jan 23, 2021·RSC Medicinal Chemistry·Antonio A W L WongDavid M Perrin
May 19, 2014·Reports of Practical Oncology and Radiotherapy : Journal of Greatpoland Cancer Center in Poznań and Polish Society of Radiation Oncology·Krzysztof Kilian

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