Abstract
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Objectives: A protecting group free approach was developed for the synthesis of a highly selective delta opioid receptor (DOR) antagonist, N1'-([11C]Methyl)Naltrindole ([11C]MeNTI). This ligand displays excellent overall selectivity (>700-fold) for DOR sites and attenuates DOR-mediated side effects e.g. tolerance, physical dependence, addiction, and constipation. The objective of the present study was to develop an improved route for the synthesis of [11C]MeNTI that does not require a benzyl protecting group [1]. The utilization of this improved method for the production of [11C]MeNTI would be beneficial to clinical research in the future.
Methods: Carbon-11 was produced as [11C]CO2 and reacted with hydrogen gas to form [11C]CH4. The generated [11C]CH4 reacted with iodine vapours at 720°C to provide [11C]MeI which was passed through a silver triflate-graphpac column to furnish desired reactive electrophilic reagent, [11C]CH3OTf. Naltrindole (NTI) was dissolved in anhydrous dimethyl formamide (DMF) and was allowed to react with [11C]CH3OTf under three different conditions.
Results: For first reaction conditions, Naltrindole (NTI) was reacted with [11C]CH3OTf at room temperature. Upon HPLC analysis, it yielded traces of desired product. Next, we decided to heat the reaction mixture at 80°C for 3 minutes, which unfortunately degraded the reaction mixture. Under both the tried methods, the radiochemical yields (RCY) were less than <0.1%. Lastly we decided to try loop chemistry at room temperature for 5 minutes. Upon completion, it was diluted with 1.0 mL of HPLC buffer and further analyzed by HPLC in-built with UV and radiation detectors. It provided the desired product [11C]MeNTI in 1% radiochemical yield (RCY). Conclusions: The present method provided a protecting group-free approach for the synthesis of [11C]MeNTI. Further optimization to improve radiochemical yield of the [11C]MeNTI, and validation for clinical production are in progress and will also be presented. References: [1] J. R. Lever, C. M. Kinter, H. T. Ravert, J. L. Musachio, W. B. Mathews, R. F. Dannals, J. Label. Compd. Radiopharm. 1994, 2, 137-145.