f-[18F]fluoroethanol and 3-[18F]fluoropropanol: facile preparation, biodistribution in mice, and their application as nucleophiles in the synthesis of [18F]fluoroalkyl aryl ester and ether PET tracers

Introduction: 2-[(18)F]Fluoroethoxy and 3-[(18)F]fluoropropoxy groups are common moieties in the structures of radiotracers used with positron emission tomography. The objectives of this study were (1) to develop an efficient one-step method for the preparation of 2-[(18)F]fluoroethanol (2-[(18)F]FEtOH) and 3-[(18)F]fluoropropanol (3-[(18)F]FPrOH); (2) to demonstrate the feasibility of using 2-[(18)F]FEtOH as a nucleophile for the synthesis of 2-[(18)F]fluoroethyl aryl esters and ethers; and (3) to determine the biodistribution profiles of 2-[(18)F]FEtOH and 3-[(18)F]FPrOH in mice.

Methods: 2-[(18)F]FEtOH and 3-[(18)F]FPrOH were prepared by reacting n-Bu4N[(18)F]F with ethylene carbonate and 1,3-dioxan-2-one, respectively, in diethylene glycol at 165°C and purified by distillation. 2-[(18)F]fluoroethyl 4-fluorobenzoate and 1-(2-[(18)F]fluoroethoxy)-4-nitrobenzene were prepared by coupling 2-[(18)F]FEtOH with 4-fluorobenzoyl chloride and 1-fluoro-4-nitrobenzene, respectively. Biodistribution and PET/CT imaging studies of 2-[(18)F]FEtOH and 3-[(18)F]FPrOH were performed in normal female Balb/C mice.

Results: The preparation of 2-[(18)F]FEtOH and 3-[(18)F]FPrOH took 60 min, and their decay-corrected yields were 88.6 ± 2.0% (n = 9) and 65.6 ± 10.2% (n = 5), respectively. The decay-corrected yields for the preparation of 2-[(18)F]fluoroethyl 4-fluorobenzoate and 1-(2-[(18)F]fluoroethoxy)-4-nitrobenzene were 36.1 ± 5.4% (n = 3) and 27.7 ± 10.7% (n = 3), respectively. Imaging/biodistribution studies in mice using 2-[(18)F]FEtOH showed high initial radioactivity accumulation in all major organs followed by very slow clearance. On the contrary, by using 3-[(18)F]FPrOH, radioactivity accumulated in all major organs was cleared rapidly, but massive in vivo defluorination (31.3 ± 9.57%ID/g in bone at 1h post-injection) was observed.

Conclusions: Using 2-[(18)F]FEtOH/3-[(18)F]FPrOH as a nucleophile is a competitive new strategy for the synthesis of 2-[(18)F]fluoroethyl/3-[(18)F]fluoropropyl aryl esters and ethers. Our biodistribution data emphasize the importance of in vivo stability of PET tracers containing a 2-[(18)F]fluoroethyl or 3-[(18)F]fluoropropyl group due to high background and high bone uptake resulting from 2-[(18)F]FEtOH and 3-[(18)F]FPrOH, respectively. This is especially important for their aryl ester derivatives which are prone to in vivo hydrolysis.