Fully Automated Radiosynthesis of Symmetric and Asymmetric [C-11]Guanidines

1455 Introduction: Guanidines are present in a variety of naturally occurring products and is a key feature of the imaging agent and radiotherapeutic Iobenguane (MIBG)1. Recently, a fully automated method has been developed for the radiosynthesis of [11C]guanidines2 in our group based on the prior work of Westerburg and Langstrom3. The automated method was able to efficiently generate terminal [11C]guanidines, and in this work we had the objective to develop a procedure for forming disubstituted [11C]guanidine that are either symmetrical or asymmetrical around the radiolabeled guanidine. Methods: Production of symmetric and asymmetric [11C]guanidines was carried out using a GE TracerLab FXm. Hydrogen [11C]cyanide from the GE PETTrace cyclotron and process panel3 was passed through a pyridinium perbromide column to form [11C]cyanogen bromide, and bubbled into the reactor containing amine precursor in sodium borate solution (pH 8.0). The reaction mixture was then heated to 80 ℃ for 5 min to afford a [11C]cyanamide intermediate2. The cyanamide intermediate was then treated with the other amine substituent of interest (e.g. 2-fluoroethylamine) and heated at 140 ℃ for 8 min to yield [11C]guanidine product (Figure 1). Results: These preliminary synthesis conditions have been fully automated with further optimization potential under investigation. Radiochemical conversion (RCC) by HPLC indicated the need to vary the concentration of the amine added in the second step, 2-fluoroethylamine, for optimization. RCC of the asymmetric guanidine was observed at 21.3% with 10 equivalent of 2-fluoroethylamine, and RCC of the symmetric guanidine peaked at 39.2%. The symmetric [11C]guanidine is an observed side product in the preparation of asymmetric guanidine. Conclusion: We have developed a reliable and fully automated radiosynthesis method for symmetric and asymmetric [11C]guanylation of amines using a commercially available radiosynthesis module. The optimization and qualification of this method to generate PET tracers for preclinical and clinical application is underway. References:[1] Guanidines Historical, Biological, Biochemical, and Clinical Aspects of the Naturally Occurring Guanidino Compounds; Mori, A., Cohen, B. D., Lowenthal, A., Eds.; Plenum Press: New York, 1985. [2] Austin Y. Zhao, Allen F. Brooks, David Raffael, Jennell Stauff, Janna Arteaga, Peter J. H. Scott, Xia Shao. Fully Automated Radiosynthesis of [11C]Guanidines as Cardiac Imaging Agents ACS Med. Chem. Lett. 2020, 11, 11, 2325-2330.[3] Westerberg, G.; Karger, W.; Onoe, H.; Langstrom, B. [11C]Cyanogen Bromide in the Synthesis of 1,3-Di(2-tolyl)-[11C]guanidine. J. Labelled Compds. Radiopharm. 1994, 34, 691-696.