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This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Chacko, A.-M. Articles by Kung, H. PubMed Articles by Chacko, A.-M. Articles by Kung, H.

Novel C-5 [¹⁸F]fluoroalkylated nucleosides for PET imaging of HSV1-tk gene expression

¹ Dept of Pharmacology; ² Dept of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania

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Objectives: In an effort to create improved PET tracers for imaging HSV1-tk reporter gene expression we have designed two novel series of pyrimidine nucleosides with (i) an F- or H-atom at the C-2' position, and (ii) a long nonpolar fluoroalkyl chain (n=3-5) at the C-5 position to better fit the HSV1-TK enzyme binding pocket. Herein, we report the radiosynthesis of C-5 [¹⁸F]fluoroalkylated nucleosides by a rapid two-step reaction, and the in vitro uptake results of these novel probes.

Methods: Six mesylate precursors were prepared in three steps from the tribenzoyl-protected derivatives of 5-iodo-2'-deoxyuridine or 2'-fluoro-2'-deoxy-1-β-D-arabinofuranosyl-5-iodouracil. The respective mesylate was fluorinated with [¹⁸F]KF in anhydrous DMF for 5 min at 135°C, followed by deprotection using NaOMe/MeOH for 5 min at 100°C. In vitro uptake studies were performed in HSV1-tk transduced RG2 (RG2TK+) cells.

Results: Radiochemical yields for 1(a-f) were 17-35% decay corrected with a total preparation time of 1-1.25 h. Radiochemical purity was >99% and specific activities of nucleosides 1(a-c)(where C-2'=H) was >1000 mCi/µmol, whereas specific activities of 1(d-f)(where C-2'=F) was 250-650mCi/µmol. LogP values for 1(a-f) were from -0.56-0.74. In vitro accumulation of 1(a-f) in RG2TK+ cells was 20, 12, 18.8, 5, 5.6 and 5-fold (P<0.001) higher than that in the control RG2 cells at 120 min respectively as compared to 8.5 and 3.7-fold higher for [¹²⁵I]FIAU and [¹⁸F]FHBG respectively.

Conclusions: The novel C-5 [¹⁸F]fluoroalkylated nucleosides can be prepared rapidly in high radiochemical yield and purity. Furthermore, the selective uptake of these PET reporter probes in target cells in vitro suggest their potential for imaging HSV1-tk gene expression in vivo.

Research Support: NIH grant R21EB005242 to HFK

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Chacko, A.-M. Articles by Kung, H. PubMed Articles by Chacko, A.-M. Articles by Kung, H.