Simple and highly efficient synthesis of 3'-deoxy-3'-[18F]fluorothymidine using nucleophilic fluorination catalyzed by protic solvent.
OBJECTIVE
The aim of this study was to develop a method of radiochemical synthesis of 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) with an improved radiochemical yield using nucleophilic substitution catalyzed by protic solvent.


METHODS
We introduced t-butanol (t-BuOH) as a new reaction solvent for nucleophilic [18F]fluorination with [18F]fluoride using (5'-O-DMTr-2'-deoxy-3'-O-nosyl-beta-D-threo-pentofuranosyl)-3-N-BOC-thymine to synthesize [18F]FLT. [18F]F- was eluted with (1) tetrabutylammonium bicarbonate (TBAHCO3), (2) Cs2CO3 and kryptofix 2.2.2 (K222) after trapping of [18F]F- on an ion exchange cartridge, or (3) addition of tetrabutylammonium hydroxide (TBAOH) and [18F]F- to the reactor without trapping [18F]F- on an ion exchange cartridge. We optimized [18F]fluorination conditions with t-butanol and then applied them to automatic synthesis using commercially available radiochemistry modules (TracerLab MX, GE Healthcare).


RESULTS
We achieved a high radiochemical yield of 85.3+/-3.5% by radio-TLC with TBAHCO3 as an elution solvent and 20 mg of precursor at 100 degrees C (n=4). With the same labeling conditions, use of Cs2CO3 and K222 with t-BuOH and TBAOH with t-BuOH generated radiochemical yields of 57.1+/-22.5% and 55.0+/-18.8% by radio-TLC, respectively (n=3 for each condition). Automated synthesis with TBAHCO3 and 20 mg of precursor at 120 degrees C for 10 min of [18F]fluorination led to radiochemical yields of 60.2+/-5.2% after HPLC purification with an MX module (n=10). Synthesized [18F]FLT was stable for 6 h.


CONCLUSIONS
[18F]FLT was synthesized with a significantly improved radiochemical yield by nucleophilic substitution catalyzed by protic solvent with mild reaction conditions and a short preparation time.
Lee
Sang Ju
SJ
Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul, 138-736, South Korea.
Oh
Seung Jun
SJ
Chi
Dae Yoon
DY
Kil
Hee Seup
HS
Kim
Euy Nyong
EN
Ryu
Jin Sook
JS
Moon
Dae Hyuk
DH
D001331:Automation; D049109:Cell Proliferation; D002855:Chromatography, Thin Layer / Q000379:methods; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D005462:Fluorine Radioisotopes / Q000737:chemistry; D054879:Halogenation; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011786:Quality Control; D011854:Radiochemistry / Q000379:methods; D019275:Radiopharmaceuticals / Q000737:chemistry*; D012997:Solvents; D013696:Temperature; D013997:Time Factors
D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D012997:Solvents; C002854:alovudine