Facile calculation of specific rate constants and activation energies of 18 F-fluorination reaction using combined processes of coat-captureeelution and microfluidics Bo Yeun Yang a, b, c , Jae Min Jeong a, b, c, * , Yun-Sang Lee a , Dong Soo Lee a, b, d , June-Key Chung a, b, c , Myung Chul Lee a, b a Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine,101 Daehangno, Jongno-gu, Seoul 110-744, South Korea b Department of Radiation Applied Life Science, Seoul National University College of Medicine, Seoul 110-744, South Korea c Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, South Korea d Department of Molecular Medicine and Biopharmaceutical Sciences, WCU Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea article info Article history: Received 4 December 2010 Received in revised form 27 January 2011 Accepted 27 January 2011 Available online 4 February 2011 Keywords: Activation energy Rate constant Microfluidics CCE process 18 F-labeling F-18 abstract Calculation of a specific rate constant (k) and activation energy (E a ) of 18 F-labeling reaction is important to obtain objective data. However, it has never been tried, because short time heating required for the calculation of the parameters was difficult. In the present study, we could calculate the parameters using combination of coat-captureeelution method (Aerts et al.) and microfluidic processes. The E a values obtained for Ts-naphthol in acetone, MeCN and t-BuOH were 5.83, 8.98, and 13.54 kcal/mol, respectively, and for Ms-naphthol in the same solvents were 5.81, 8.16, and 19.34kcal/mol, respectively. Calculation of these parameters might be useful for setting up [ 18 F]fluorination procedure and for developing new precursors. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Positron emission tomography (PET) is an influential modality for molecular imaging, 1 and 18 F-labeled agents, such as [ 18 F]FDG are the most important and widely used probes for PET. And thus the development of 18 F-labeling methods has been always hot issue for PET, and as the demand for PET increase, it requires more effective synthesis methods for radio tracers. 2 Most 18 F-labeling reactions are nucleophilic substitution using [ 18 F]fluoride produced by bombardment of [ 18 O]water with accel- erated proton. 3,4 Generally, [ 18 F]fluoride is captured on an anion exchange resin and then eluted with base solution such as K 2 CO 3 / Kryptofix 2.2.2 (K222) or tetrabutylammonium bicarbonate (TBAB) (Fig. 1a). The base solution should contain significant amount of water to elute ionic bonded [ 18 F]fluoride from the anion resin. And thus obtained [ 18 F]fluoride is highly solvated with water, which prevents nucleophilic substitution reaction. So, the water should be removed to activate [ 18 F]fluoride, and azeotropic evaporation by heating under reduced pressure with inert gas flow is the most common procedure, which requires time and significant size re- action vessel. Therefore the evaporation step is the most challenging process for automation and microfluidics system for 18 F-labeling. Several trials have been reported to exclude the evaporation step. For example, a special quaternary ammonium solid-phase resin was developed. 5 In this report, 18 F is captured on the resin, water is removed by washing with organic solvent, and then 18 F- labeling is performed on the solid phase system with continuous flow of precursor solution in organic solvent. However, this method was suffered with low and fluctuating labeling yields, because the reaction on a solid phase is significantly slower than the solution- phase reaction. Another trial was using ionic liquid without evap- oration step, 6 however, this method has problems due to high viscosity of ionic liquid and residual ionic liquid in the final product. An electrochemical cell method can exclude evaporation step, however, it requires specially designed electrochemical cell. 7 A la- beling method by formation of [ 18 F]aluminum fluoride chelate 8,9 do not need evaporation step, because this reaction occurs in aqueous solution. However, its application field is limited for some special * Corresponding author. Tel.: þ822 2072 3805; fax: þ822 745 7690; e-mail address: jmjng@snu.ac.kr (J.M. Jeong). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.01.088 Tetrahedron 67 (2011) 2427e2433