Good Manufacturing Practice Validation and Radiation Dosimetry for the Clinical Application of a Novel α7-nAChR Radioligand: [11C]KIn83
Abstract
:1. Introduction
- (i)
- GMP-compliant Production Verification: To pave the way for potential clinical use, we rigorously verified the Good Manufacturing Practice (GMP) compliance of the [11C]Kln83 production process. This validation encompassed a comprehensive review of all aspects of the manufacturing process, from raw materials and synthesis procedures to quality control measures and final product specifications. Meeting GMP standards ensures consistent production of a high-quality, safe, and efficacious radiopharmaceutical, which is vital for its successful transition into clinical settings.
- (ii)
- Dosimetry Assessment: To ensure the safe and effective application of [11C]Kln83 in human studies, we conducted dosimetry assessments using data obtained from whole-body PET scans in non-human primates (NHPs). This crucial step involved meticulously evaluating the distribution and clearance of the radioligand within the NHPs’ bodies, allowing us to calculate the radiation dose received by various organs and tissues. The data obtained from these assessments will be essential for determining the optimal dosage for human studies, minimizing radiation exposure while maximizing diagnostic efficacy.
2. Results and Discussion
2.1. Radiochemistry, Validation, and CMC
2.2. Whole-Body PET
3. Materials and Methods
3.1. Synthesis of [11C]KIn83
3.2. Process Validation of [11C]KIn83
3.3. Quality Control (QC)
3.3.1. Pre-Release QC Tests
3.3.2. Post-Release QC Tests
3.4. Whole-Body PET Measurements in NHP
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Region of Interest | NHP 1 | NHP 2 |
---|---|---|
Brain | 61 | 73 |
Lungs | 106 | 124 |
Kidneys | 22 | 27 |
Spleen | 8 | 6 |
Gall Bladder | 3 | 12 |
Liver | 114 | 96 |
Heart | 29 | 32 |
Urinary Bladder | 23 | 3 |
Intestine | 391 | 489 |
Vertebrae | 6 (93) | 5 (74) |
Thyroid | 0.5 | 1 |
Salivary Glands | 4 | 3 |
Region of Interest | NHP 1 | NHP 2 | Average |
---|---|---|---|
Brain | 0.00566 | 0.00491 | 0.00528 |
Lungs | 0.01343 | 0.01192 | 0.01267 |
Kidneys | 0.01546 | 0.03546 | 0.02546 |
Spleen | 0.00252 | 0.00147 | 0.00200 |
Gall Bladder | 0.00282 | 0.03805 | 0.02044 |
Liver | 0.06469 | 0.05895 | 0.06182 |
Heart | 0.00483 | 0.00600 | 0.00542 |
Urinary Bladder | 0.00969 | 0.00136 | 0.00553 |
Intestine | 0.05216 | 0.03639 | 0.04428 |
Vertebrae | 0.00984 | 0.00755 | 0.00870 |
Thyroid | 0.00056 | 0.00028 | 0.00042 |
Salivary Glands | 0.00125 | 0.00064 | 0.00094 |
Target Organ | Alpha | Beta | Gamma | Total | ICRP-103 ED |
---|---|---|---|---|---|
Adrenals | 0.00 | 1.45 × 10−3 | 4.79 × 10−3 | 6.24 × 10−3 | 5.76 × 10−5 |
Brain | 0.00 | 8.45 × 10−4 | 8.24 × 10−4 | 1.67 × 10−3 | 1.67 × 10−5 |
Breasts | 0.00 | 1.10 × 10−3 | 1.20 × 10−3 | 2.30 × 10−3 | 2.76 × 10−4 |
Esophagus | 0.00 | 1.00 × 10−3 | 2.10 × 10−3 | 3.10 × 10−3 | 1.24 × 10−4 |
Eyes | 0.00 | 1.00 × 10−3 | 9.02 × 10−4 | 1.90 × 10−3 | 0.00 |
Gallbladder Wall | 0.00 | 4.42 × 10−2 | 1.39 × 10−2 | 5.81 × 10−2 | 5.36 × 10−4 |
Left colon | 0.00 | 1.00 × 10−3 | 3.07 × 10−3 | 4.07 × 10−3 | 1.97 × 10−4 |
Small Intestine | 0.00 | 1.68 × 10−2 | 4.77 × 10−3 | 2.16 × 10−2 | 1.99 × 10−4 |
Stomach Wall | 0.00 | 1.01 × 10−3 | 2.41 × 10−3 | 3.43 × 10−3 | 4.11 × 10−4 |
Right colon | 0.00 | 1.01 × 10−3 | 3.27 × 10−3 | 4.28 × 10−3 | 2.08 × 10−4 |
Rectum | 0.00 | 1.00 × 10−3 | 2.07 × 10−3 | 3.07 × 10−3 | 7.06 × 10−5 |
Heart Wall | 0.00 | 2.42 × 10−3 | 2.44 × 10−3 | 4.86 × 10−3 | 4.49 × 10−5 |
Kidneys | 0.00 | 1.89 × 10−2 | 6.35 × 10−3 | 2.53 × 10−2 | 2.33 × 10−4 |
Liver | 0.00 | 8.62 × 10−3 | 5.63 × 10−3 | 1.43 × 10−2 | 5.70 × 10−4 |
Lungs | 0.00 | 2.58 × 10−3 | 1.93 × 10−3 | 4.51 × 10−3 | 5.42 × 10−4 |
Ovaries | 0.00 | 1.10 × 10−3 | 2.44 × 10−3 | 3.54 × 10−3 | 1.41 × 10−4 |
Pancreas | 0.00 | 1.03 × 10−3 | 3.76 × 10−3 | 4.79 × 10−3 | 4.42 × 10−5 |
Prostate | 0.00 | 9.03 × 10−4 | 1.78 × 10−3 | 2.68 × 10−3 | 1.24 × 10−5 |
Salivary Glands | 0.00 | 2.58 × 10−3 | 1.26 × 10−3 | 3.84 × 10−3 | 3.84 × 10−5 |
Red Marrow | 0.00 | 1.25 × 10−3 | 1.77 × 10−3 | 3.03 × 10−3 | 3.63 × 10−4 |
Osteogenic Cells | 0.00 | 1.23 × 10−3 | 1.62 × 10−3 | 2.86 × 10−3 | 2.86 × 10−5 |
Spleen | 0.00 | 3.15 × 10−3 | 2.80 × 10−3 | 5.95 × 10−3 | 5.49 × 10−5 |
Testes | 0.00 | 9.03 × 10−4 | 1.01 × 10−3 | 1.91 × 10−3 | 7.65 × 10−5 |
Thymus | 0.00 | 1.03 × 10−3 | 1.68 × 10−3 | 2.70 × 10−3 | 2.49 × 10−5 |
Thyroid | 0.00 | 4.76 × 10−3 | 1.60 × 10−3 | 6.36 × 10−3 | 2.54 × 10−4 |
Urinary Bladder Wall | 0.00 | 4.37 × 10−3 | 2.18 × 10−3 | 6.55 × 10−3 | 2.62 × 10−4 |
Uterus | 0.00 | 1.10 × 10−3 | 2.71 × 10−3 | 3.80 × 10−3 | 1.76 × 10−5 |
Total Body | 0.00 | 1.65 × 10−3 | 1.51 × 10−3 | 3.16 × 10−3 | 0.00 |
Effective Dose | 4.77 × 10−3 |
Test Procedure | Acceptance Criteria | Method Reference |
---|---|---|
pH a | 4.5–8.5 | pH indicator paper |
Radioactivity a | To be reported | Dose calibrator |
Product identification a | Rt Radiopeak—Rt UV ≤ 0.30 min | HPLC |
Radiochemical purity a | Not less than 95% | HPLC |
Molar activity a | To be reported | HPLC |
Chemical amount of KIn83 a | The mass does not exceed 20 µg per injected dose b | HPLC |
Total amount of UV-absorbing impurities including precursor a | The mass does not exceed 20.0 µg per injected dose b | HPLC |
Filter integrity a | Millex GV not less than 3.5 bar | Bubble point test |
Sterility c | Sterile according to Ph Eur | Ph Eur |
Bacterial endotoxins d | Less than 14.5 IU/mL | Endosafe PTS |
Residual solvents d | ||
Acetone | Not more than 50 mg | GC |
Ethanol | Not more than 100000 ppm | GC |
Acetonitrile | Not more than 4.1 mg | GC |
DMF | Not more than 8.8 mg | HPLC |
Radionuclidic identity e | Half-life 18.3 to 22.4 min | Dose calibrator |
Radiochemical stability e | Not less than 95% radiochemical purity after 60 | HPLC |
Appearance f | Clear and colorless solution free from visual particulates | Visual inspection |
Settle plate d | 0 CFU | Ph Eur |
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Jia, Z.; Bolin, M.; Morén, A.F.; Datta, P.; Asem, H.; Ågren, H.; Långström, B.; Nordberg, A.; Halldin, C.; Nag, S. Good Manufacturing Practice Validation and Radiation Dosimetry for the Clinical Application of a Novel α7-nAChR Radioligand: [11C]KIn83. Molecules 2025, 30, 1356. https://doi.org/10.3390/molecules30061356
Jia Z, Bolin M, Morén AF, Datta P, Asem H, Ågren H, Långström B, Nordberg A, Halldin C, Nag S. Good Manufacturing Practice Validation and Radiation Dosimetry for the Clinical Application of a Novel α7-nAChR Radioligand: [11C]KIn83. Molecules. 2025; 30(6):1356. https://doi.org/10.3390/molecules30061356
Chicago/Turabian StyleJia, Zhisheng, Martin Bolin, Anton Forsberg Morén, Prodip Datta, Heba Asem, Hans Ågren, Bengt Långström, Agneta Nordberg, Christer Halldin, and Sangram Nag. 2025. "Good Manufacturing Practice Validation and Radiation Dosimetry for the Clinical Application of a Novel α7-nAChR Radioligand: [11C]KIn83" Molecules 30, no. 6: 1356. https://doi.org/10.3390/molecules30061356
APA StyleJia, Z., Bolin, M., Morén, A. F., Datta, P., Asem, H., Ågren, H., Långström, B., Nordberg, A., Halldin, C., & Nag, S. (2025). Good Manufacturing Practice Validation and Radiation Dosimetry for the Clinical Application of a Novel α7-nAChR Radioligand: [11C]KIn83. Molecules, 30(6), 1356. https://doi.org/10.3390/molecules30061356