Direct Methylation with [11C]CO2 for Production of Radiopharmaceuticals

Project Summary Positron Emission Tomography (PET) is an imaging modality that can be used to visualize and quantify functional changes and the distribution of molecular markers in the body. PET utilizes molecules that are labeled with positron-emitting isotopes (radiotracers), which are typically produced via automated synthesis modules. Carbon-11 (11C) is a particularly important PET radionuclide, as virtually all organic molecules contain carbon atoms. Because 11C has the same properties as carbon-12, labeling with 11C is extremely useful as a radionuclide for exploration of molecules as PET radiopharmaceuticals for exploration of their in vivo properties (metabolism, binding, pharmacokinetics, etc.). Furthermore, the short half-life of 11C (20.3 min) allows for the possibility of multiple molecular imaging studies on the same day, simplifying the logistics and recruitment for clinical research studies. Traditionally, 11C is installed with either [11C]Mel or [11C]MeOTf as synthons due to their straightforward production from cyclotron-produced [11C]CO2. Recently, researchers have begun to use [11C]CO2 directly to form ureas and carbamates, but exploration into use of [11C]CO2 for methylation has been extremely limited. In this proposal we will: 1) Develop and optimize direct use of [11C]CO2 reductive methylation method for heteroatoms using a silicon-hydride reduction system. It is expected that this approach will provide facile and rapid access to 11C-radiopharmaceuticals with a broad substrate scope; 2) Develop a site-specific labeling method using iminophosphorances and [11C]CO2 that will allow for 11C-methylation in the presence of multiple reactive sites; 3) Extend this direct [11C]CO2 methylation methodology to carbon-nucleophiles to allow for direct carbon methylation using [11C]CO2. Development of these radiosynthesis methods will allow for more reliable and straightforward 11C-labeling strategies, reducing the development timeline for new 11C-radiopharmaceuticals and improving the radiochemical yields.