Synthesis of 11C-Labelled PET Radiotracers via [11C]CO2 fixation

1063 Objectives There is significant interest in the development of carbon-11 labeling methods that enable synthesis of radiotracers in 1- or 2-steps directly from [11C]CO2. This approach reduces synthesis time and associated losses in radioactivity when compared to 11C synthon-based methods, and can also permit the labeling of bioactive molecules not possible with current methods. Herein we report three new variants of [11C]CO2 fixation that are used to provide access to three novel radiotracers that are important to our neuroimaging and translational oncology programs: [11C]3-(3-(1H-imidazol-1-yl)propyl)quinazoline-2,4(1H,3H)-dione ([11C]QZ, 1), [11C]tideglusib (2), and [11C]ibrutinib (3). Methods Precursors and reference standards were synthesized via modified literature procedures or purchased from commercial suppliers. [11C]CO2 was produced with a PETTrace cyclotron via the 14N(p,α)11C reaction. Radiolabeling of precursors with [11C]CO2 was conducted with TRACERLab FXc-pro synthesis modules according to the Scheme. HPLC and TLC were used to validate product identity and determine radiochemical yield. Results [11C]QZ (target: glutaminyl cyclase, 1% RCY, >99% RCP, 3 Ci/mmol) was prepared by treating a substituted 2-aminobenzamide precursor with [11C]CO2 and BEMP, followed by POCl3 to facilitate intramolecular cyclization. MicroPET imaging of [11C]QZ conducted in a rodent, however, showed no brain uptake. [11C]Tideglusib (target: glycogen synthase kinase-3, 3% RCY) was prepared by treating 1-naphthylamine with [11C]CO2 and BEMP followed by POCl3 to form [11C]naphthylisocyanate. This was then treated with benzylisothiocyanate and N-chlorosuccinimide to form the 1,2,4-thiadiazolidine-3,5-dione core. On purification, [11C]tideglusib was observed to decompose through an unknown but presumably radiolytic pathway. [11C]Ibrutinib (Bruton’s tyrosine kinase, 2-5% RCY, >90% RCP, 600-2100 Ci/mmol) was prepared through a HATU peptide coupling of an amino precursor with [11C]acrylic acid (generated from [11C]CO2 fixation with vinylmagnesium bromide). In an initial baseline PET study, [11C]ibrutinib showed significant uptake and retention in spleen, liver and intestines, consistent with the known distribution and excretion of ibrutinib. Conclusions Conclusions: This work demonstrates several methods to rapidly trap [11C]CO2, which allows for quite sophisticated downstream chemistry to take place in spite of the 20 min half-life of carbon-11. These new methods enabled the synthesis and characterization of three clinically-relevant yet previously inaccessible 11C labeled radiopharmaceuticals. Acknowledgements: PJHS acknowledges US DOE/NIBIB (DE-SC0012484), NIH (T32-EB005172) and the Alzheimer’s Association (NIRP-14-305669) for financial support. Ibrutinib precursor and reference standard were generously provided by Bristol-Myers Squibb.