Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y2 Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies
Abstract
:1. Introduction
2. Results and Discussion
2.1. Batch Synthesis
2.2. Continuous Flow Synthesis
2.3. Radiochemistry
2.4. PET Imaging
3. Materials and Methods
3.1. Materials
3.2. Instrumentation
3.3. Synthesis of N-Me-JNJ-31020028
3.4. Radiochemistry
3.5. Pre-Clinical Studies
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Entry | Stoichiometry (Equiv. of CH3I) | Temperature (°C) | Residence Time (min) | Flow Rate (mL/min) | Conversion (%) (b),(c) | Yield (%) (b),(c) |
---|---|---|---|---|---|---|
1 | 1.5 | 25 | 25 | 0.4 | 82 ± 3.8 | 64 ± 7.2 |
2 | 1.5 | 25 | 10 | 1.0 | 99 ± 0.6 | 87 ± 3.5 |
3 | 1.5 | 25 | 5 | 2.0 | 99 ± 1.0 | 90 ± 1.5 |
4 | 1.5 | 25 | 3 | 3.3 | 99 ± 1.5 | 88 ± 2.5 |
5 | 1.5 | 40 | 5 | 2.0 | 97 ± 2.0 | 92 ± 1.5 |
6 | 3.0 | 25 | 5 | 2.0 | 98 ± 2.0 | 81 ± 3.2 |
7 | 3.0 | 40 | 5 | 2.0 | 98 ± 1.5 | 77 ± 7.6 |
Entry | Stoichiometry (Equiv. of CH3I) | Temperature (°C) | Residence Time (min) | Flow Rate (mL/min) | Conversion (%) (b),(c) | Yield (%) (b),(c) |
---|---|---|---|---|---|---|
1 | 1.5 | 25 | 5 | 0.3 | 66 ± 2.1 | 60 ± 4.9 |
2 | 1.5 | 40 | 5 | 0.3 | 94 ± 2.0 | 88 ± 0.6 |
3 | 3.0 | 40 | 5 | 0.3 | 95 ± 1.0 | 89 ± 1.5 |
4 | CH3I (gas) | 40 | 5 | 0.3 | 98 ± 3.2 | 67 ± 5.3 |
Entry | Base | Temperature (°C) | Stirring | Reaction Time (min) | [11C]2 (%) (a),(b) | RCY (d.c) (%) (b),(c) |
---|---|---|---|---|---|---|
1 (d) | NaH (0.02 mg/mL) | 50 | Yes | 3 | 90.4 ± 0.65 | 41.8 ± 1.06 |
2 | NaH (0.02 mg/mL) | 50 | Yes | 3 | 85.4 ± 5.69 | 39.9 ± 0.68 |
3 | NaH (0.02 mg/mL) | 50 | No | 3 | 81.1 ± 7.77 | 37.4 ± 1.22 |
4 | NaH (0.02 mg/mL) | 50 | Yes | 5 | 78.4 ± 14.95 | 34.4 ± 5.06 |
5 | NaOH (5M) | 50 | No | 5 | 91.2 ± 3.04 | 38.3 ± 4.37 |
6 | NaOH (5M) | 50 | Yes | 5 | 68.7 ± 11.77 | 26.4 ± 3.66 |
7 | NaOH (5M) | 75 | No | 5 | 88.5 ± 6.30 | 41.0 ± 4.8 |
8 | NaOH (5M) | 75 | Yes | 5 | 80.3 ± 8.27 | 33.0 ± 7.83 |
9 (e) | NaOH (5M) | rt | No | 5 | 98.7 ± 1.14 | 31.3 ± 1.07 (f) |
Tests | Specifications | N-[11C]-Me-JNJ31020028-1 | N-[11C]-Me-JNJ31020028-2 | N-[11C]-Me-JNJ31020028-3 |
---|---|---|---|---|
Appearance | Clear, colourless solution | Comply | Comply | Comply |
pH after dilution | 4.5–8.5 | 6.4 | 6.4 | 6.5 |
Chemical purity | ||||
N-Me-JNJ31020028 | ≥95% | 100% | 100% | 100% |
Radiochemical purity | ||||
N-[11C]-Me-JNJ31020028 | ≥95% | 99.2% | 99.9% | 99.4% |
Radionuclidic purity | ||||
Radionuclidic identification − Energy photons ϒ | The only gamma photons have energy of 0.511 MeV. A sum peak of 1.022 MeV may be observed | Comply | Comply | Comply |
Half-life | 19.9 to 20.9 min | 20.1 | 20.2 | 20.2 |
Residual Solvents | ||||
Ethanol | ≤2500 mg/10 mL (a) | 491.2 | 900.8 | 504.2 |
Acetonitrile | ≤4 mg/10 mL | 2.9 | 2.0 | 0.8 |
Biological Tests | ||||
Sterility (b) | No evidence of microbial growth should be found | Comply | Comply | Comply |
Bacterial endotoxins | ≤175 IU/10 mL | Comply | Comply | Comply |
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Fonseca, I.C.F.; Pais, M.L.; Rodrigues, F.M.S.; Sereno, J.; Castelo-Branco, M.; Cavadas, C.; Pereira, M.M.; Abrunhosa, A.J. Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y2 Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies. Pharmaceuticals 2024, 17, 474. https://doi.org/10.3390/ph17040474
Fonseca ICF, Pais ML, Rodrigues FMS, Sereno J, Castelo-Branco M, Cavadas C, Pereira MM, Abrunhosa AJ. Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y2 Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies. Pharmaceuticals. 2024; 17(4):474. https://doi.org/10.3390/ph17040474
Chicago/Turabian StyleFonseca, Inês C. F., Mariana Lapo Pais, Fábio M. S. Rodrigues, José Sereno, Miguel Castelo-Branco, Cláudia Cavadas, Mariette M. Pereira, and Antero J. Abrunhosa. 2024. "Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y2 Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies" Pharmaceuticals 17, no. 4: 474. https://doi.org/10.3390/ph17040474
APA StyleFonseca, I. C. F., Pais, M. L., Rodrigues, F. M. S., Sereno, J., Castelo-Branco, M., Cavadas, C., Pereira, M. M., & Abrunhosa, A. J. (2024). Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y2 Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies. Pharmaceuticals, 17(4), 474. https://doi.org/10.3390/ph17040474