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.
Highlights
The onward progress in the field of anti-tumor therapies led to increased interest in radiodiagnostics for selecting appropriate therapeutics and for the assessment of therapy success. [18F]fluorodeoxyglucose (FDG) in PET analysis is a gold standard for detecting vital tumor tissue, in the brain difficulties arise from the high physiologic uptake in healthy tissue resulting in decreased sensitivity and localizing validity for cerebral tumors
We investigated the stability of the synthesized tracers against thymidine phosphorylase in vitro (Table 1)
Previous studies identified three important aspects that need to be considered for the development of novel cerebral tumor tracers based on the IUdR structure
Summary
The onward progress in the field of anti-tumor therapies led to increased interest in radiodiagnostics for selecting appropriate therapeutics and for the assessment of therapy success. [18F]fluorodeoxyglucose (FDG) in PET analysis is a gold standard for detecting vital tumor tissue, in the brain difficulties arise from the high physiologic uptake in healthy tissue resulting in decreased sensitivity and localizing validity for cerebral tumors.Beside amino acid tracers [1,2,3], radiolabeled DNA building blocks, thymidine analogues in particular have been tested for localizing brain tumors with promising results [4,5]. Investigations on the metabolism revealed that IUdR tracers are rapidly degraded and that the elimination of the deoxyribose residue leading to 5iodouracil (5-IU), and therewith to the loss of DNA integration properties, is the rate-limiting process [7] To circumvent this obstacle a variety of IUdR analogues have been synthesized and tested in vivo for their abilities as tumor tracing agents. An exchange of the ring oxygen atom in the deoxyribose leading to 49-thio-29-deoxyuridine derivatives revealed more promising results, yielding a high metabolic stability and acceptable DNA incorporation rates These derivatives showed a reduced phosphorylation by thymidine kinase 1 implicating an increased background radioactivity and, revealed a decreased cell uptake in different tumor cell lines [8,9]. Previous studies clearly demonstrate strict limitations in varying the structure of IUdR to attain useful new tumor tracing agents
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