Isotopologues of potassium 2,2,2-trifluoroethoxide for applications in positron emission tomography and beyond

• Published in: Nature communications Vol. 15; no. 1; pp. 5798 - 10
• Main Authors: Zhao, Qunchao, Telu, Sanjay, Jana, Susovan, Morse, Cheryl L., Pike, Victor W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 140/58; 639/638/403/933; 639/638/549/933; 692/4017; Aliphatic compounds; Carbon Radioisotopes - chemistry; Drug development; Drug discovery; Drugs; Fluorine; Fluorine Radioisotopes - chemistry; Formaldehyde; Humanities and Social Sciences; Humans; Isotopic labeling; Medical imaging; multidisciplinary; Polymers; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Potassium; Potassium - chemistry; Radioactive tracers; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Science; Science (multidisciplinary); Stable isotopes; Substrates; Tomography; Tracers; Transition metals; Trifluoromethane
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49975-7

The 2,2,2-trifluoroethoxy group increasingly features in drugs and potential tracers for biomedical imaging with positron emission tomography (PET). Herein, we describe a rapid and transition metal-free conversion of fluoroform with paraformaldehyde into highly reactive potassium 2,2,2-trifluoroethoxide (CF 3 CH 2 OK) and demonstrate robust applications of this synthon in one-pot, two-stage 2,2,2-trifluoroethoxylations of both aromatic and aliphatic precursors. Moreover, we show that these transformations translate easily to fluoroform that has been labeled with either carbon-11 ( t 1/2  = 20.4 min) or fluorine-18 ( t 1/2  = 109.8 min), so allowing the appendage of complex molecules with a no-carrier-added 11 C- or 18 F- 2,2,2-trifluoroethoxy group. This provides scope to create candidate PET tracers with radioactive and metabolically stable 2,2,2-trifluoroethoxy moieties. We also exemplify syntheses of isotopologues of potassium 2,2,2-trifluoroethoxide and show their utility for stable isotopic labeling which can be of further benefit for drug discovery and development. The 2,2,2-trifluoroethoxy group features in drugs and potential tracers for biomedical imaging with positron emission tomography. Herein, the authors report the conversion of fluoroform into potassium 2,2,2-trifluoroethoxide isotopologues and their applications in late stage 2,2,2-trifluoroethoxylations of aromatic and aliphatic substrates for positron emission tomography and stable isotope labeling.