Recent efforts have been made to develop alternatives to the most common radiopharmaceutical used in positron emission tomography (PET), 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), for evaluating tumorigenesis. One such alternative is 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT), a 18F-labeled thymidine analog that serves as an imaging biomarker of cellular proliferation. Goals of this study were to implement and optimize an automated synthesis for [18F]FLT at St. Jude Children’s Research Hospital (SJCRH) and to perform in vivo PET imaging to validate the usefulness of [18F]FLT as a marker for cellular proliferation. Methods: [18F]FLT chemistry was performed on an IBA Synthera® automated radiosynthesis instrument via a three-step process: 1) [18F]fluorination, 2) deprotection, and 3) neutralization. The phase transfer base and the precursor solvent for the [18F]fluorination step were optimized. Fluorinated intermediate product yields were determined by TLC with radioactivity detection, and [18F]FLT product yields were calculated by analytical HPLC with radioactivity detection. Mice (n=6) with right-rear flank tumors were injected with [18F]FLT (~100µCi). After 40min following injection, 4 mice were imaged on a Siemens Inveon small animal PET/CT scanner. At 1hr following injection, all mice were dissected, and the tissues were weighed and counted for radioactivity in an automated gamma counter to measure the biodistribution of [18F]FLT. Results: Of all the phase transfer bases tested, tetrabutyl ammonium bicarbonate (TBAB) resulted in the greatest fluorinated intermediate yield. Use of 3-methyl-3-pentanol (MEP) as a precursor co-solvent significantly increased the fluorinated intermediate yield (from 37±3% to 66±6%). Under the optimized conditions, [18F]FLT was synthesized with a final yield of 48±2%, radiochemical purity of &gt;99.9%, and synthesis time of 48±1min. As expected, the greatest uptake of [18F]FLT in the mice took place in the right-rear flank tumor, kidneys, and spleen, while the smallest uptake was in the brain. Conclusion: The use of TBAB as a phase transfer base and MEP as a precursor co-solvent afforded high yields of the fluorinated intermediate (66±6%). With the optimized conditions, [18F]FLT product yields increased more than three-fold from the initial synthesis performed at SJCRH. Finally, the in vivo study validated the efficacy of [18F]FLT as a proliferation marker and confirmed [18F]FLT as a promising alternative to [18F]FDG.

Improved radiosynthesis of 3’-deoxy-3’-[18F]fluorothymidine and its in vivo application as a proliferation imaging marker in positron emission tomography

253rd National Meeting (2017)

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