N(3)-Substituted thymidine analogues V: synthesis and preliminary PET imaging of N(3)-[(18)F]fluoroethyl thymidine and N(3)-[(18)F]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/mumol 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.

• Authors: Uday Mukhopadhyay, Suren Soghomonyan, Hsin Hsien Yeh, Leo G Flores, Aleksandr Shavrin, Andrei Y Volgin, Juri G Gelovani, Mian M Alauddin
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 35 Issue 6 Pg. 697-705 (Aug 2008) ISSN: 0969-8051 [Print] United States
• PMID: 18678355 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• N(3)-fluoropropylthymidine
• O-(2-fluoroethyl)tyrosine
• Radiopharmaceuticals
• Tyrosine
• Thymidine

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (diagnostic imaging, metabolism)
• Cell Line, Tumor
• Humans
• Metabolic Clearance Rate
• Mice
• Mice, Nude
• Organ Specificity
• Pilot Projects
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (pharmacokinetics)
• Thymidine (analogs & derivatives, pharmacokinetics)
• Tissue Distribution
• Tyrosine (analogs & derivatives, pharmacokinetics)