Abstract
BackgroundNitrogen-13 has a 10-min half-life which places time constraints on the complexity of viable synthetic methods for its incorporation into PET imaging agents. In exploring ways to overcome this limitation, we have used the Ugi reaction to develop a rapid one-pot method for radiolabelling peptidic molecules using [13N]NH3 as a synthetic precursor.MethodsCarrier-added [13N]NH3 (50 μL) was added to a solution of carboxylic acid, aldehyde, and isocyanide in 2,2,2-TFE (200 μL). The mixture was heated in a microwave synthesiser at 120 °C for 10 min. Reactions were analysed by radio-HPLC and radio-LCMS. Isolation of the target 13N–labelled peptidic Ugi compound was achieved via semi-preparative radio-HPLC as demonstrated for Ugi1.ResultsRadio-HPLC analysis of each reaction confirmed the formation of radioactive products co-eluting with their respective reference standards with radiochemical yields of the crude products ranging from 11% to 23%. Two cyclic γ-lactam structures were also achieved via intra-molecular reactions. Additional radioactive by-products observed in the radio-chromatogram were identified as 13N–labelled di-imines formed from the reaction of [13N]NH3 with two isocyanide molecules. The desired 13N–labelled Ugi product was isolated using semi-preparative HPLC.ConclusionWe have developed a one-pot method that opens up new routes to radiolabel complex, peptidic molecules with 13N using aqueous [13N]NH3 as a synthetic precursor.
Highlights
Nitrogen-13 has a 10-min half-life which places time constraints on the complexity of viable synthetic methods for its incorporation into positron emission tomography (PET) imaging agents
Radiochemistry Radiosynthesis of 1–5 was achieved via the Ugi reaction by combining benzaldehyde, the respective carboxylic acid and isocyanide, and carrier-added aqueous [13N]NH3 (Fig. 1)
The optimum solvent was found to be TFE, affording radiochemical yields (RCY, based on radio-HPLC analysis of the crude product) of 13%, performing better than MeCN (9%), while Dimethyl formamide (DMF) afforded no yield (Table 1, entries 1–3)
Summary
Nitrogen-13 has a 10-min half-life which places time constraints on the complexity of viable synthetic methods for its incorporation into PET imaging agents. In exploring ways to overcome this limitation, we have used the Ugi reaction to develop a rapid one-pot method for radiolabelling peptidic molecules using [13N]NH3 as a synthetic precursor. Compared to other cyclotron-produced positron emitters such as 18F and 11C, 13N has been largely overlooked as a viable option for radiolabelling as its short half-life poses challenges to the development of synthetic methods. The Ugi reaction is an attractive method for the rapid radiolabelling of peptides with short-lived PET radionuclides, useful in diagnosis, drug discovery and as a research tool in understanding molecular mechanisms in vivo. We report the radiolabelling of α-aminoacyl amide derivatives with 13N, via the four-component coupling (4-CC) Ugi synthesis, using aqueous [13N]NH3 as a precursor
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