Kenneth Dahl

An evaluation of a high‐pressure 11CO carbonylation apparatus

[(11)C]Carbon monoxide ((11)CO) is a versatile building block for the synthesis of Positron Emission Tomography (PET) radioligands. However, the difficulty of trapping (11)CO in a small solvent volume has limited its utility. We here report an evaluation of a simple, fully automated high-pressure synthesizer prototype for the use in (11)C-carbonylation reactions. [(11)C]Carbon monoxide was easily prepared by online reduction of [(11)C]carbon dioxide using either Mo(s) or Zn(s) as the reducing agent. The conversion yield of (11)CO was >99% when zinc was used as the reducing agent, and the corresponding value for Mo was approximately 71%. When the Zn or Mo column was constantly kept under inert atmosphere, no significant decrease in reducing properties was observed for more than 100 (11)CO productions. However, in our hands, Mo reductant was much easier to service. A total of nine functional groups were successfully radiolabeled using the (11)CO synthesizer prototype. All measured radiochemical yields exceeded 37%, and the (11)CO trapping efficiency was generally above 90%, except for the Suzuki coupling where the trapping efficiency was 80%. This high-pressure synthesizer using [(11)C]carbon monoxide as the labeling precursor is easy to operate allowing for (11)C-carbonylation reactions to be performed in a high yield and in a routinely fashion.

New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals.

PurposeThis short review aims to cover the more recent and promising developments of carbon-11 (11C) labeling radiochemistry and its utility in the production of novel radiopharmaceuticals, with special emphasis on methods that have the greatest potential to be translated for clinical positron emission tomography (PET) imaging.MethodsA survey of the literature was undertaken to identify articles focusing on methodological development in 11C chemistry and their use within novel radiopharmaceutical preparation. However, since 11C-labeling chemistry is such a narrow field of research, no systematic literature search was therefore feasible. The survey was further restricted to a specific timeframe (2000–2016) and articles in English.ResultsFrom the literature, it is clear that the majority of 11C-labeled radiopharmaceuticals prepared for clinical PET studies have been radiolabeled using the standard heteroatom methylation reaction. However, a number of methodologies have been developed in recent years, both from a technical and chemical point of view. Amongst these, two protocols may have the greatest potential to be widely adapted for the preparation of 11C-radiopharmaceuticals in a clinical setting. First, a novel method for the direct formation of 11C-labeled carbonyl groups, where organic bases are utilized as [11C]carbon dioxide-fixation agents. The second method of clinical importance is a low-pressure 11C-carbonylation technique that utilizes solvable xenon gas to effectively transfer and react [11C]carbon monoxide in a sealed reaction vessel. Both methods appear to be general and provide simple paths to 11C-labeled products.ConclusionRadiochemistry is the foundation of PET imaging which relies on the administration of a radiopharmaceutical. The demand for new radiopharmaceuticals for clinical PET imaging is increasing, and 11C-radiopharmaceuticals are especially important within clinical research and drug development. This review gives a comprehensive overview of the most noteworthy 11C-labeling methods with clinical relevance to the field of PET radiochemistry.

11C-carbonylation reactions using gas–liquid segmented microfluidics

A novel gas–liquid segmented microfluidic platform has been developed. The Pd-mediated 11C-carbonylation reaction proceeds smoothly on this platform and good to excellent radiochemical conversions (RCC) were observed. Twelve compounds were successfully radiolabelled using this novel technology, including the well established D2 receptor radioligands [11C]raclopride and [11C]FLB 457.

Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18 F-isotopologue validated our liver-targeting approach.

CCDC 1569471: Experimental Crystal Structure Determination

Related Article: Kim F. McClure, David W. Piotrowski, Donna Petersen, Liuqing Wei, Jun Xiao, Allyn T. Londregan, Adam S. Kamlet, Anne-Marie Dechert-Schmitt, Brian Raymer, Roger B. Ruggeri, Daniel Canterbury, Chris Limberakis, Spiros Liras, Paul DaSilva-Jardine, Robert G. Dullea, Paula M. Loria, Benjamin Reidich, Christopher T. Salatto, Heather Eng, Emi Kimoto, Karen Atkinson, Amanda King-Ahmad, Dennis Scott, Kevin Beaumont, Jeffrey R. Chabot, Michael W. Bolt, Kevin Maresca, Kenneth Dahl, Ryosuke Arakawa, Akihiro Takano, Christer Halldin|2017|Angew.Chem.,Int.Ed.|56|16218|doi:10.1002/anie.201708744

An evaluation of a high-pressure (11)CO carbonylation apparatus.

[(11)C]Carbon monoxide ((11)CO) is a versatile building block for the synthesis of Positron Emission Tomography (PET) radioligands. However, the difficulty of trapping (11)CO in a small solvent volume has limited its utility. We here report an evaluation of a simple, fully automated high-pressure synthesizer prototype for the use in (11)C-carbonylation reactions. [(11)C]Carbon monoxide was easily prepared by online reduction of [(11)C]carbon dioxide using either Mo(s) or Zn(s) as the reducing agent. The conversion yield of (11)CO was >99% when zinc was used as the reducing agent, and the corresponding value for Mo was approximately 71%. When the Zn or Mo column was constantly kept under inert atmosphere, no significant decrease in reducing properties was observed for more than 100 (11)CO productions. However, in our hands, Mo reductant was much easier to service. A total of nine functional groups were successfully radiolabeled using the (11)CO synthesizer prototype. All measured radiochemical yields exceeded 37%, and the (11)CO trapping efficiency was generally above 90%, except for the Suzuki coupling where the trapping efficiency was 80%. This high-pressure synthesizer using [(11)C]carbon monoxide as the labeling precursor is easy to operate allowing for (11)C-carbonylation reactions to be performed in a high yield and in a routinely fashion.

An evaluation of a high-pressure11CO carbonylation apparatus: High-pressure11CO carbonylation apparatus

[(11)C]Carbon monoxide ((11)CO) is a versatile building block for the synthesis of Positron Emission Tomography (PET) radioligands. However, the difficulty of trapping (11)CO in a small solvent volume has limited its utility. We here report an evaluation of a simple, fully automated high-pressure synthesizer prototype for the use in (11)C-carbonylation reactions. [(11)C]Carbon monoxide was easily prepared by online reduction of [(11)C]carbon dioxide using either Mo(s) or Zn(s) as the reducing agent. The conversion yield of (11)CO was >99% when zinc was used as the reducing agent, and the corresponding value for Mo was approximately 71%. When the Zn or Mo column was constantly kept under inert atmosphere, no significant decrease in reducing properties was observed for more than 100 (11)CO productions. However, in our hands, Mo reductant was much easier to service. A total of nine functional groups were successfully radiolabeled using the (11)CO synthesizer prototype. All measured radiochemical yields exceeded 37%, and the (11)CO trapping efficiency was generally above 90%, except for the Suzuki coupling where the trapping efficiency was 80%. This high-pressure synthesizer using [(11)C]carbon monoxide as the labeling precursor is easy to operate allowing for (11)C-carbonylation reactions to be performed in a high yield and in a routinely fashion.