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Objectives
In the last few years new emerging metal-mediated radiolabeling methods have facilitated access to probes which had been so far inaccessible or difficult to produce using conventional labeling procedures. Particularly, procedures for copper-mediated 18F-fluorination discovered by Gouverneur et al. [1] and further developed by inventors and others [2]. On the other hands, a guideline called ICH-Q3D regulates the permission limit of elemental impurities in conventional drugs. Hence, we should consider and prepare to reflect such regulation into daily radio-pharmaceutical productions. The most common detection technique for metal (elements) impurity is inductively coupled plasma mass spectrometry (ICP-MS) detection. Although ICP-MS is a suitable instrument to analyze trace amount of metallic impurities with high sensitivity, it is cumbersome for routine assessment. We report here the metal impurity in PET probe measured by using the HPLC post-column method.
Methods
Production of [18F]DOPA by copper-mediated method was performed using homemade automation single reactor module. The residual amount of copper in the final solution were analyzed using a metal-free JASCO Extrema HPLC system (Tokyo, Japan) including two pumps, auto sampler, column-oven, and a UV–VIS detector. One pump was used to deliver MetPac PDCA eluent through the analytical column, and the other one was used to deliver PAR diluent. The sample solution was separated through an IonPac CS5A analytic column (4.6 × 250mm), and the eluent mixed with the dye PAR was analyzed by the UV–VIS detector at 520 nm of copper. Flow rates for MetPac PDCA eluent and PAR diluent solution were 1.2 mL/min and 0.6 mL/min, respectively. Calibration curves for copper ranging from 10 to 2000 μg/L were made from the TraceCERT® ICP-MS standard at an injection volume of 50 μL.
Results
The concentration of copper was measured with a good linearity in the range of 10 to 2000 μg/mL (R2>0.98), repeatability on three injections at the same day in less than 5% relative standard deviation (% RSD). We enabled detecting the residual amount of copper in [18F]DOPA using the HPLC post-column system, and calculate the residual amount of copper in [18F]DOPA (0.03 ppm±0.01ppm). This is significantly below any level of concern according to the ICH Guideline of Elemental Impurities (Q3D). We will report the residual amount of copper in [11C]product using copper-mediated cyanation.
Conclusions
The post-column evaluation provided considerable sensitivity for metal impurity within a short time (10 min), suggesting that this method is suitable for daily QC because of the simplicity and prompt measurement. Therefore, we used the data obtained by the post-column method only for estimating metal impurity of PET probe in a daily QC protocol.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number 18K07281.
Reference
[1] Tredwell, M., et al., Angew. Chem. 2014, 126, 1-6.
[2] Zarrad, F., et al., Molecules 2017, 22, 2231; doi:10.3390/molecules22122231.
Measurement of the metal impurity in PET probe using the HPLC post-column method
