N³-Substituted thymidine analogues V: Synthesis and preliminary PET imaging of N³-[¹⁸F]fluoroethyl thymidine and N³-[¹⁸F]fluoropropyl thymidine

Abstract 

Introduction

[¹⁸F]-Labeled analogues of thymidine have demonstrated efficacy for PET imaging of cellular proliferation. We have synthesized two [¹⁸F]-labeled N³-substituted thymidine analogues, N³-[¹⁸F]fluoroethyl thymidine (N³-[¹⁸F]-FET) and N³-[¹⁸F]fluoropropyl thymidine (N³-[¹⁸F]-FPrT), and performed preliminary PET imaging studies in tumor-bearing mice.

Methods

Thymidine was converted to its 3′,5′-O-bis-tetrahydropyranyl ether, which was then converted to the N³-ethyl and propyl-substituted mesylate precursors. Reactions of these mesylate precursors with n-Bu₄N[¹⁸F] or K[¹⁸F]/kryptofix followed by acid hydrolysis and HPLC purification yielded N³-[¹⁸F]-FET and N³-[¹⁸F]-FPrT, respectively. Subcutaneous (sc) xenografts of H441 human non–small cell lung cancer were established in two groups of mice (each n=6). Micro-PET images of the tumor-bearing animals were acquired after intravenous injection of N³-[¹⁸F]-FET or N³-[¹⁸F]-FPrT (3700 KBq/animal).

Results

The radiochemical yields were 2–12% (d.c.) for N³-[¹⁸F]-FET and 30–38% (d.c.) for N³-[¹⁸F]-FPrT. Radiochemical purity was >99% and calculated specific activity was >74 GBq/μmol at the end of synthesis. The accumulation of N³-[¹⁸F]-FET and N³-[¹⁸F]-FPrT in the tumor tissue at 2 h postinjection was 1.81±0.78 and 2.95±1.14 percent injected dose per gram (%ID/g), respectively; tumor/muscle ratios were 5.57±0.82 and 7.69±2.18, respectively; the unidirectional influx rates (K_i) were 0.013 and 0.018 ml/g per minute, respectively.

Conclusion

Two novel [¹⁸F]- N³-substituted thymidine analogues have been synthesized in good yields, high purity and high specific activity. Preliminary in vivo studies demonstrated the efficacy of these [¹⁸F]- N³-substituted thymidine analogues for PET imaging of tumors.

Keywords: Fluorine-18, Thymidine, Tumor, Proliferation, PET