title: Synthesis and evaluation of a radiometal-labeled macrocyclic chelator-derivatised thymidine analog.
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.
authors.affiliation: Department of Nuclear Medicine, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schmid
authors.forename: Bernd
authors.initials: B
authors.lastname: Neumaier
authors.forename: Andreas T J
authors.initials: AT
authors.lastname: Vogg
authors.forename: Katrin
authors.initials: K
authors.lastname: Wczasek
authors.forename: Claudia
authors.initials: C
authors.lastname: Friesen
authors.forename: Felix M
authors.initials: FM
authors.lastname: Mottaghy
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Buck
authors.forename: Sven N
authors.initials: SN
authors.lastname: Reske
mesh_terms: D002614:Chelating Agents / Q000737:chemistry; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics*; D018922:HL-60 Cells / Q000187:drug effects; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics*; D008024:Ligands; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D010766:Phosphorylation; D013379:Substrate Specificity; D013936:Thymidine / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013937:Thymidine Kinase / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C493794:1,4,7-tris(tert-butylacetate)-1,4,7,10-tetraazacyclododecane ester; D002614:Chelating Agents; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D008024:Ligands; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine