2-[¹⁸F]Fluoroethanol and 3-[¹⁸F]fluoropropanol: Facile preparation, biodistribution in mice, and their application in the radiosynthesis of PET tracers

Objectives 2-[¹⁸F]Fluoroethoxy and 3-[¹⁸F]fluoropropoxy groups are common moieties in the structures of PET tracers. The goals of this study were to develop an efficient one-step method for the preparation of 2-[¹⁸F]fluoroethanol (2-[¹⁸F]FEtOH) and 3-[¹⁸F]fluoropropanol (3-[¹⁸F]FPrOH), and to demonstrate the feasibility of using 2-[¹⁸F]FEtOH as a nucleophile for the synthesis of 2-[¹⁸F]fluoroethyl aryl ester and ether.

Methods 2-[¹⁸F]FEtOH and 3-[¹⁸F]FPrOH were prepared by reacting n-Bu₄N[¹⁸F]F with ethylene carbonate and 1,3-dioxan-2-one, respectively, and purified by distillation. 2-[¹⁸F]fluoroethyl 4-fluorobenzoate and 1-(2-[¹⁸F]fluoroethoxy)-4-nitrobenzene were prepared by coupling 2-[¹⁸F]FEtOH with 4-fluorobenzoyl chloride and 1-fluoro-4-nitrobenzene, respectively.

Results The preparation of 2-[¹⁸F]FEtOH and 3-[¹⁸F]FPrOH took 60 min, and their decay-corrected yields were > 85 and 58-82 %, respectively. The decay-corrected yields for the preparation of 2-[¹⁸F]fluoroethyl 4-fluorobenzoate and 1-(2-[¹⁸F]fluoroethoxy)-4-nitrobenzene were 32-42 % (n = 3) and 17-38 % (n = 3), respectively. Imaging/biodistribution studies in mice showed that uptakes of 2-[¹⁸F]FEtOH were high in all major organs (5.4-10.3 %ID/g) at 2 min p.i. followed by slow clearance (3.9-7.3 %ID/g at 1 h p.i.). On the contrary, 3-[¹⁸F]FPrOH was cleared rapidly from all major organs (< 1.7 % ID/g at 1 h p.i.) and excreted mainly via the renal pathway, but showed significant in vivo defluorination (10.7 %ID/g in bone at 1 h p.i.).

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