TY - JOUR T1 - Design and Prototype of an Automated "In-loop" [<sup>11</sup>C]CO<sub>2</sub>-Fixation Apparatus JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 330 LP - 330 VL - 58 IS - supplement 1 AU - Kenneth Dahl AU - Thomas Collier AU - Xiaofei Zhang AU - Steven Liang AU - Neil Vasdev Y1 - 2017/05/01 UR - http://jnm.snmjournals.org/content/58/supplement_1/330.abstract N2 - 330Objectives: [11C]Carbon dioxide ([11C]CO2) is a highly attractive building block for radiolabeling, since it is produced directly in target. However, due to low chemical reactivity and trapping efficiency, the direct incorporation of [11C]CO2 into organic molecules poses a significant challenge. More recently, a novel method for the direct formation of 11C-labelled carbonyl groups has become established in routine radiopharmaceutical production, where organic bases, e.g. DBU or BEMP, are utilized as [11C]CO2-fixation agents prior to the covalent bond formation. [11C]CO2 fixation radiochemistry has been restricted by semi-manual methods, therefore our aim is to develop a fully automated [11C]CO2-fixation apparatus, and to take advantage of “in-loop” technologies for facilitate robust and reproducible delivery of 11C-carbonyl based radiotracers.Methods: A module for in-loop [11C]CO2-fixation was designed and produced as a prototype to evaluate its feasibility. All components were purchased from commercial sources (e.g. valves, lift, mass-flow controller (MFC), heaters). In a typical experiment, cyclotron produced [11C]CO2 was first trapped in a stainless steel (1-m, 1/16 in) coil cooled with liquid nitrogen. The accumulated [11C]CO2 was transferred into the stainless steel HPLC loop (2.5 mL, 1/16 in) pre-coated with a fixation solution (BEMP + amine precursor dissolved in 80 µL DMF) using a controlled stream of N2 (20 mL/min, via MFC). Trapping of radioactivity in the loop was monitored by a proximal radiation detector. When the radioactivity peaked in the loop (1-2 min), the flow of N2 was stopped and the reaction was allowed to proceed for additional 1-5 min. The content of the reaction loop was eluted out with a second reagent (alkylating or dehydrating agent) dissolved in anhydrous CH3CN using a constant N2 flow. The product receiving vial was either kept empty or pre-charged with a nucleophile, e.g. amine or alcohol, to furnish the final 11C-carbonyl labelled product. Compound identity was confirmed using radio-HPLC and LC-MS.Results: The in-loop [11C]CO2-fixation method consists of trapping and reacting [11C]CO2 direct in a stainless steel loop, has been applied in the synthesis of 11C-carbonyl-groups with diverse scaffolds including a 11C-carbamate, 11C-oxazolidinone, and three 11C-ureas in good radiochemical conversions (RCC) ranging from 30-98%. Structurally similar 11C-isotopologs of pharmaceuticals were labeled, including the fatty acid amide hydrolase (FAAH) inhibitor, [11C]JNJ1661010, in 69% RCC. In all cases this automated in loop methodology enabled us to obtain equal or superior yields compared with conventional semi-automated reactions in a vial. The method proceeds smoothly without any manual manipulations and all reactions are carried out at ambient temperature and pressure. To illustrate the utility of this present method, [11C]JNJ1661010 was produced in a preparative scale, yielding the isolated product in a decay-corrected radiochemical yield of 55% (14.5 GBq; 392 mCi) relative to [11C]CO2. The radiochemical purity was &gt;99% and the specific activity was 40 GBq/µmol (1081 Ci/mmol) in an overall synthesis time of 38 min.Conclusion: We herein described the development of the first fully automated [11C]CO2-fixation apparatus which proved to be useful for diverse 11C-carbonylation, including 11C-oxazolidinones, 11C-ureas and 11C-carbamates. This novel “in-loop” [11C]CO2 fixation method is simple, efficient, and enables the reliable production of diverse 11C-carbonylation with minimal loss in radioactivity. Research Support: ER -