title: Diesterified derivatives of 5-iodo-2'-deoxyuridine as cerebral tumor tracers.
abstract: With the aim to develop beneficial tracers for cerebral tumors, we tested two novel 5-iodo-2'-deoxyuridine (IUdR) derivatives, diesterified at the deoxyribose residue. The substances were designed to enhance the uptake into brain tumor tissue and to prolong the availability in the organism. We synthesized carrier added 5-[125I]iodo-3',5'-di-O-acetyl-2'-deoxyuridine (Ac2[125I]IUdR), 5-[125I]iodo-3',5'-di-O-pivaloyl-2'-deoxyuridine (Piv2[125I]IUdR) and their respective precursor molecules for the first time. HPLC was used for purification and to determine the specific activities. The iodonucleoside tracer were tested for their stability against human thymidine phosphorylase. DNA integration of each tracer was determined in 2 glioma cell lines (Gl261, CRL2397) and in PC12 cells in vitro. In mice, we measured the relative biodistribution and the tracer uptake in grafted brain tumors. Ac2[125I]IUdR, Piv2[125I]IUdR and [125I]IUdR (control) were prepared with labeling yields of 31-47% and radiochemical purities of >99% (HPLC). Both diesterified iodonucleoside tracers showed a nearly 100% resistance against degradation by thymidine phosphorylase. Ac2[125I]IUdR and Piv2[125I]IUdR were specifically integrated into the DNA of all tested tumor cell lines but to a less extend than the control [125I]IUdR. In mice, 24 h after i.p. injection, brain radioactivity uptakes were in the following order Piv2[125I]IUdR>Ac2[125I]IUdR>[125I]IUdR. For Ac2[125I]IUdR we detected lower amounts of radioactivities in the thyroid and stomach, suggesting a higher stability toward deiodination. In mice bearing unilateral graft-induced brain tumors, the uptake ratios of tumor-bearing to healthy hemisphere were 51, 68 and 6 for [125I]IUdR, Ac2[125I]IUdR and Piv2[125I]IUdR, respectively. Esterifications of both deoxyribosyl hydroxyl groups of the tumor tracer IUdR lead to advantageous properties regarding uptake into brain tumor tissue and metabolic stability.
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps-University, Marburg, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rösler
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps-University, Marburg, Germany; Institute of Neuroscience and Medicine (INM-2), Research Center Jülich, Jülich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Matusch
authors.affiliation: Department of Nuclear Medicine, Philipps-University, Marburg, Germany.
authors.forename: Damiano
authors.initials: D
authors.lastname: Librizzi
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps-University, Marburg, Germany; Department of Neurology, Technical University, Munich, Germany.
authors.forename: Oscar
authors.initials: O
authors.lastname: Arias-Carrión
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps-University, Marburg, Germany; Brain Imaging and Neurostimulation (BINS) Laboratory, Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Freundlieb
authors.affiliation: Department of Nuclear Medicine, Philipps-University, Marburg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hoeffken
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps-University, Marburg, Germany.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps-University, Marburg, Germany.
authors.forename: Candan
authors.initials: C
authors.lastname: Depboylu
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps-University, Marburg, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Department of Neurology, Technical University, Munich, Germany.
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000175:diagnosis*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004951:Esterification; D006801:Humans; D007065:Idoxuridine / Q000737:chemistry* / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D011849:Radioactive Tracers; D013939:Thymidine Phosphorylase / Q000378:metabolism
chemical_list: D007457:Iodine Radioisotopes; D011849:Radioactive Tracers; D013939:Thymidine Phosphorylase; D007065:Idoxuridine