Optimization of the Automated Synthesis of [11C]mHED—Administered and Apparent Molar Activities
<p>Correlation of the myocardium/intra-ventricular blood pool ratio and the molar activity, the mass of residual precursor and non-labelled <span class="html-italic">m</span>HED, as well as the sum of both.</p> "> Figure 2
<p>Representative cardiac images in short axis orientation of rat hearts (infarct model) with different applied mass doses of metaraminol and <span class="html-italic">m</span>HED. The sum of metaraminol and <span class="html-italic">m</span>HED is shown beneath the respective image.</p> "> Figure 3
<p>Correlation of the myocardium/intra-ventricular blood pool ratio (<b>left</b>) and correlation between the myocardium/mediastinum ratio (<b>right</b>) and the molar activity, the mass of residual precursor and non-labelled <span class="html-italic">m</span>HED, as well as the sum of both (Morbus Fabry patients).</p> "> Figure 4
<p>Cardiac images (short axis orientation) of Morbus Fabry patients with different applied mass doses of metaraminol and <span class="html-italic">m</span>HED. The sum of metaraminol and <span class="html-italic">m</span>HED is shown beneath the respective image. The patient with abnormality of sympathetic innervation was excluded in the figure, showing a Myo/Med ratio of <4 with an applied mass dose of 4.5 µg.</p> "> Figure 5
<p>Correlation of the myocardium/intra-ventricular blood pool ratio (<b>left</b>) and correlation between the myocardium/mediastinum ratio (<b>right</b>) and the molar activity, the mass of residual precursor and non-labelled <span class="html-italic">m</span>HED, as well as the sum of both (heart transplantation (HTX) patients).</p> "> Figure 6
<p>Overview on the radiosynthesis optimization, including the challenges and establishments during the first 44 syntheses and the stable separation process of the last 51 syntheses.</p> "> Figure 7
<p>Reaction scheme of the radiosynthesis of [<sup>11</sup>C]<span class="html-italic">m</span>HED.</p> "> Figure 8
<p>Typical chromatogram of the semi-preparative RP-HPLC purification of the crude mixture: The [<sup>11</sup>C]<span class="html-italic">m</span>HED elutes after 9.5 min from the C-18 RP column after using a step gradient, as illustrated at the top of the graphic. Solvent A consists of an acetonitrile:water mixture (58:42) and solvent B is a mixture of acetonitrile and acidified water (50:50; 0.004% H<sub>3</sub>PO<sub>4</sub>, conc).</p> "> Figure 9
<p>Calibration curve for metaraminol and <span class="html-italic">m</span>HED. Concentrations were chosen in the range of 0.1–5 µg/mL.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Radiosynthesis of [11C]mHED
2.2. µPET/µCT Imaging
2.3. PET/MRI Imaging
3. Discussion
4. Material and Methods
4.1. Radiosynthesis
4.2. Semi-Preparative Purification
4.3. Quality Control
4.4. Animal Preparation
4.5. Imaging of µPET/µCT
4.6. PET/MRI Imaging
4.7. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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[11C]mHED | Starting Activity [GBq] | Yield [GBq] | Yield [%EOB] | Molar Activity [GBq/µmol mHED] | Precursor Concentration [µg/mL] | mHED Concentration [µg/mL] |
---|---|---|---|---|---|---|
All synthesis (n = 32) | 114 ± 15 | 3 ± 2 | 2.5 ± 1.5 | 126 ± 97 | 8 ± 7 | 3 ± 8 |
Patients: | ||||||
Morbus Fabry (n = 5) | 124 ± 2 | 3.5 ± 0.4 | 2.9 ± 0.3 | 155 ± 85 | 6 ± 4 | 2 ± 1 |
HTX (n = 9) | 120 ± 2 | 2.3 ± 1.3 | 2 ± 1 | 129 ± 148 | 5.5 ± 3.8 | 1.7 ± 2.8 |
Animals (n = 11) | 122 ± 3 | 3 ± 2 | 2.4 ± 1.9 | 211 ± 152 | 4.6 ± 4.7 | 9 ± 19 |
[11C]mHED | Metaraminol | mHED | ||
---|---|---|---|---|
Patients | [µg/applied volume] | [µg/kg BW] | [µg/applied volume] | [µg/kg BW] |
Morbus Fabry (n = 5) | 5.2 ± 3.3 | 0.06 ± 0.05 | 1.6 ± 1.3 | 0.02 ± 0.02 |
HTX (n = 9) | 5.5 ± 3.8 | 0.1 ± 0.1 | 2.1 ± 1.5 | 0.02 ± 0.02 |
Animals (n = 11) | 1.8 ± 2.9 | 4.9 ± 8.4 | 0.8 ± 1.8 | 1.8 ± 3.8 |
Rosenspire et al. 1990 | Nagren et al. 1995 | Van Dort et al. 2000 | Law et al. 2010 | This work | |
---|---|---|---|---|---|
Methylation agent | [11C]CH3I | [11C]CH3OTf | [11C]CH3I | According to Rosenspire et al. | [11C]CH3OTf |
250 µL DMF:DMSO (3:1) | 100 µL ACN | anhydrous DMF 150 µL | 250 µL DMF:DMSO (3:1) | DMF:DMSO (4:1, v/v%) | |
[c] Precursor | 1 mg metaraminol free base, freshly prepared from metaraminol bitartrate | 1 mg free base | 0.6 mg free base | 1 mg free base | 1 mg free base |
Formulation | 10% EtOH + 0.24 M NaH2PO4, ~7 mL | physiological phosphate buffer 8 mL | 0.04 M NaH2PO4 10 mL | According to Rosenspire et al. | 0.9% saline 3 mL |
[c] Metaraminol | 21 µg mean | Not reported | Not reported | 2 µM | 8 ± 7 µg/mL |
[c] mHED | Not reported | Not reported | 9 µM | 3 ± 8 µg/mL | |
Radiochemical purity% | 98 2% unidentified RI | Not reported | >98 | 95 ± 5 | 98 ± 2 |
Time of synthesis (EOB) | 45 min without evaporation | Approx. 41 min | 40 min | According to Rosenspire et al. | 30–35 min |
Molar activity (EOS) [GBq/µmol] | 33 ± 18 (n = 19) | Not reported | 47–60 (mean = 51) (n = 8) | 10–30 | 126 ± 97 (n = 32) |
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Vraka, C.; Pichler, V.; Berroterán-Infante, N.; Wollenweber, T.; Pillinger, A.; Hohensinner, M.; Fetty, L.; Beitzke, D.; Li, X.; Philippe, C.; et al. Optimization of the Automated Synthesis of [11C]mHED—Administered and Apparent Molar Activities. Pharmaceuticals 2019, 12, 12. https://doi.org/10.3390/ph12010012
Vraka C, Pichler V, Berroterán-Infante N, Wollenweber T, Pillinger A, Hohensinner M, Fetty L, Beitzke D, Li X, Philippe C, et al. Optimization of the Automated Synthesis of [11C]mHED—Administered and Apparent Molar Activities. Pharmaceuticals. 2019; 12(1):12. https://doi.org/10.3390/ph12010012
Chicago/Turabian StyleVraka, Chrysoula, Verena Pichler, Neydher Berroterán-Infante, Tim Wollenweber, Anna Pillinger, Maximilian Hohensinner, Lukas Fetty, Dietrich Beitzke, Xiang Li, Cecile Philippe, and et al. 2019. "Optimization of the Automated Synthesis of [11C]mHED—Administered and Apparent Molar Activities" Pharmaceuticals 12, no. 1: 12. https://doi.org/10.3390/ph12010012