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

Abstract Introduction [ 18 F]-Labeled analogues of thymidine have demonstrated efficacy for PET imaging of cellular proliferation. We have synthesized two [ 18 F]-labeled N 3 -substituted thymidine analogues, N 3 -[ 18 F]fluoroethyl thymidine (N 3 -[ 18 F]-FET) and N 3 -[ 18 F]fluoropropyl thymidine (N 3 -[ 18 F]-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 N 3 -ethyl and propyl-substituted mesylate precursors. Reactions of these mesylate precursors with n-Bu 4 N[ 18 F] or K[ 18 F]/kryptofix followed by acid hydrolysis and HPLC purification yielded N 3 -[ 18 F]-FET and N 3 -[ 18 F]-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 N 3 -[ 18 F]-FET or N 3 -[ 18 F]-FPrT (3700 KBq/animal). Results The radiochemical yields were 2–12% (d.c.) for N 3 -[ 18 F]-FET and 30–38% (d.c.) for N 3 -[ 18 F]-FPrT. Radiochemical purity was >99% and calculated specific activity was >74 GBq/μmol at the end of synthesis. The accumulation of N 3 -[ 18 F]-FET and N 3 -[ 18 F]-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 [ 18 F]- N 3 -substituted thymidine analogues have been synthesized in good yields, high purity and high specific activity. Preliminary in vivo studies demonstrated the efficacy of these [ 18 F]- N 3 -substituted thymidine analogues for PET imaging of tumors.