An improved strategy for the synthesis of [18F]-labeled arabinofuranosyl nucleosides

Abstract

The expression of the herpes simplex virus type-1 thymidine kinase (HSV1-tk) gene can be imaged efficaciously using a variety of 2′-[18F]fluoro-2′-deoxy-1-b-D-arabinofuranosyl-uracil derivatives [[18F]-FXAU, X= I(iodo), E(ethyl), and M(methyl)]. However, the application of these derivatives in clinical and translational studies has been impeded by their complicated and long syntheses (3–5 h). To remedy these issues, in the study at hand we have investigated whether microwave or combined catalysts could facilitate the coupling reaction between sugar and nucleobase and, further, have probed the feasibility of establishing a novel approach for [18F]-FXAU synthesis. We have demonstrated that the rate of the trimethylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed coupling reaction between the 2-deoxy-sugar and uracil derivatives at 90°C can be significantly accelerated by microwave-driven heating or by the addition of Lewis acid catalyst (SnCl4). Further, we have observed that the stability of the α- and β-anomers of [18F]-FXAU derivatives differs during the hydrolysis step. Using the microwave-driven heating approach, overall decay-corrected radiochemical yields of 19–27% were achieved for [18F]-FXAU in 120 min at a specific activity of >22 MBq/nmol (595 Ci/mmol). Ultimately, we believe that these high yielding syntheses of [18F]-FIAU, [18F]-FMAU and [18F]-FEAU will facilitate routine production for clinical applications.

Comparative Analysis of T Cell Imaging with Human Nuclear Reporter Genes

“…18 F-MFBG (~19 GBq/mmol) ( 15 ), 18 F-FEAU (~22 GBq/μmol) ( 28 ), carrier-free 124 I-MIBG (>12 GBq/μmol), carrier-free 124 I-iodide, and carrier-free 124 I-FIAU were synthesized at Memorial Sloan Kettering Cancer Center ( 28 ). 123 I-MIBG (clinical formulation) was obtained from Nuclear Diagnostics Products.…”

Comparative Analysis of Human Nucleoside Kinase-Based Reporter Systems for PET Imaging

“…Preparations of [ 18 F]FEAU and [ 124 I]FIAU were described previously [18]. L-[ 18 F]FEAU was synthesized according to the protocol for [ 18 F]FEAU, except using the starting precursor (2- O -[(trifluormethyl)sulfonyl]-1,3,5-tri- O -benzoyl-alpha-L-ribofuranose instead of 2- O -[(trifluormethyl)sulfonyl]-1,3,5-tri- O -benzoyl-alpha-D-ribofuranose).…”

Fluorine-18 labelled building blocks for PET tracer synthesis

“…218,221 The reaction time of 60 minutes was rather long, and led to low overall yields. 222 Although this method is described as very reliable, major disadvantages such as the use of corrosive hydrogen bromide make it not amenable for clinical production. Therefore, an alternative method suitable for automated synthesis of [ 18 F]FXAU has been developed, which employs trimethylsilyl trifluoromethanesulfonate (TMSOTf) as Friedel Crafts catalyst in the coupling reaction that enables direct coupling between building block 303 and silyl precursor 305.…”

“…Though, neither microwave heating nor the use of SnCl 4 influenced the anomeric ratio positively. 222 In conclusion, synthesis of the building block 2-deoxy-2- After deprotection with citric acid, the product was purified by semi-preparative HPLC to afford PC-[ 18 In the follow-up aldol condensation, 312 was reacted with a 5-hydroxy-1-phenyl-hexa-1,4-dien-3-one (313) in the presence of B 2 O 3 , (n-BuO) 3 B and piperidine at 120 1C. After treatment with hydrochloric acid, the final product 314 was purified by semipreparative HPLC and obtained in a radiochemical yield of 15-25% with a specific activity of 37.6 GBq mmol À1 .…”