A general ¹¹C-carboxylation approach mediated by fluoride-desilylation of organosilanes

Introduction: A novel synthetic pathway for [¹¹C]acetoacetic acid ([¹¹C]AcAc) was developed in our laboratory recently. Compared to the organolithium ¹¹C-carboxylation method, which may generate more chemical impurities due to the use of highly reactive organolithium reagent, this fluoride ion mediated desilylation process generated the enolate in-situ and reacted with [¹¹C]CO₂ in a mild and fast fashion. The desired [¹¹C]AcAc was formed in 24 - 30 min with a decay-corrected radiochemical yield (dcRCY) of 50 - 65% and a radiochemical purity (RCP) of 94 - 97%. Based upon this research, we intended to develop a fluoride-desilylation mediated (FDSM) ¹¹C-carboxylation approach, with which we can quickly synthesize structurally diversified ¹¹C-labeled carboxylic acids with ¹¹C attached at different hybridized carbons (sp, sp² and sp³).

Methods: The synthesis of propiolic-[1-¹¹C]acids using alkynyltrimethylsilanes and CsF for sp-hybridized carbanion generation was first explored, followed by the preparation of ¹¹C-labeled ester and amide using ¹¹C-carboxylate prepared by FDSM approach. Next, different organosilanes with trialkylsilyl group attached at both sp² and sp³ carbons were tested and optimal reaction conditions were screened for synthesizing the corresponding ¹¹C-carboxylic acids. The synthesis of two potentially metabolic relevant PET imaging tracers, [¹¹C]succinic acid and [¹¹C]dichloroacetic acid, were explored at the end of this research.

Results: Twelve propiolic-[1-¹¹C]acids with different functional groups attached were synthesized under mild reaction conditions (THF/DMSO, 40 ^oC, 5 min) in good to excellent radiochemical conversion yields (RCC, 60 - 99%). Meanwhile, the quick conversion of ¹¹C-carboxylic acids to their ester and amide derivatives was demonstrated by successful synthesis of 3-pyridyl attached methyl [1-¹¹C]propiolate and 3-chlorophenyl attached [1-¹¹C]propiolyl benzylamide. Moreover, thirteen aryl/heteroaryl and eleven alkyl ¹¹C-carboxylic acids with broad structural diversity were synthesized under significantly varied reaction conditions (reaction temperature ranging from -78 to 200 ^oC) and in dramatically different RCC (1.4% - 96%). Two synthetically challenging molecules of biological and clinical interest, [¹¹C]succinic acid and [¹¹C]dichloroacetic acid, were synthesized using FDSM ¹¹C-carboxylation method in practically acceptable yields (RCY, 50.1 ± 12.3% & 31.8 ± 3.1%, n = 3).

Conclusions: A robust and novel FDSM ¹¹C-carboxylation method has been developed. The simplicity, high degree of reproducibility, and broad scope of the transformation of this approach, as demonstrated by the ¹¹C-labeling of various organic carboxylic acids and their derivatives, makes it a highly attractive synthetic strategy in radiotracer chemistry. The further application of this method will be showcased in the near future. Acknowledgements: This work was supported by the Radiology Department, Weill Cornell Medicine (WCM) (Internal research fund for W.Q. and B.H.). Both Howard Sheh and Calvin Lom are acknowledged for cyclotron operation to supply [¹¹C]CO₂ radioactivity.

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