Preparation and Preclinical Evaluation of 18F-Labeled Olutasidenib Derivatives for Non-Invasive Detection of Mutated Isocitrate Dehydrogenase 1 (mIDH1)
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry and Radiochemistry
2.1.1. Synthesis of Reference Compound (4) and Radiolabeling Precursors (11, 18, 19) for the Preparation of [18F]mIDH-138 ([18F]4)
2.1.2. Radiosynthesis of [18F]mIDH-138 ([18F]4)
2.1.3. Synthesis of Reference Compounds [(S)- and (R)-2] and Radiolabeling Precursors [(S)- and (R)-29, (S)- and (R)-30] for (S)- and (R)-[18F]mIDH-23 [(S)- and (R)-[18F]2]
2.1.4. Radiosynthesis of (S)- and (R)-[18F]mIDH-23 [(S)- and (R)-[18F]2]
2.1.5. Synthesis of Reference Compound (5) and Radiolabeling Precursor (39) for [18F]FE-mIDH-138 ([18F]5)
2.1.6. Radiosynthesis of [18F]FE-mIDH-138 ([18F]5)
2.2. In Vitro Evaluation
2.2.1. Lipophilicity
2.2.2. In Vitro Stability
2.2.3. Inhibitory Potency
2.2.4. Cellular Uptake and Localization
2.3. In Vivo Evaluation of [18F]mIDH-138 ([18F]4)
2.3.1. Biodistribution Studies in Healthy C57BL/6 Mice
2.3.2. Biodistribution Studies in CB17-SCID Mice with Subcutaneous U87-WT and U87-mIDH Tumors
3. Materials and Methods
3.1. Chemistry and Radiochemistry
3.2. Cell Culture and In Vitro Studies
3.2.1. Cell Culture and Reagents
3.2.2. 2-Hydroxyglutarate (2-HG) Assays
3.2.3. Determination of Lipophilicity
3.2.4. Determination of Stability in DMSO
3.2.5. Determination of Stability in PBS
3.2.6. Determination of Stability in Rat Serum
3.2.7. Determination of Inhibitory Potency
3.2.8. Cellular Uptake Studies
3.3. In Vivo Studies
3.3.1. Animals
3.3.2. Subcutaneous Tumor Model
3.3.3. PET Measurements
3.3.4. Kinetic Modelling
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Tracer | logP | logD7.4 | |
---|---|---|---|
Exp. Determined | ADMETlab | ||
(S)-[18F]mIDH-23 [(S)-[18F]2] | negative | 2.51 ± 0.11 | 2.33 |
(R)-[18F]mIDH-23 [(R)-[18F]2] | negative | 2.51 ± 0.11 | 2.33 |
[18F]mIDH-138 ([18F]4) | 2.50 ± 0.03 | 2.67 ± 0.04 | 2.75 |
[18F]FE-mIDH-138 ([18F]5) | 2.77 ± 0.03 | 2.72 ± 0.06 | 2.87 |
Timeframe | SUVbw | Ratio (WT/mIDH) | Significance 1 | |
---|---|---|---|---|
U87-WT | U87-mIDH | |||
0–30 min | 35 ± 4 | 31 ± 3 | 1.1 | p = 0.5810 |
30–60 min | 42 ± 9 | 24 ± 2 | 1.7 | p = 0.0031 |
60–90 min | 36 ± 10 | 18 ± 1 | 1.9 | p = 0.0033 |
90–120 min | 30 ± 10 | 16 ± 1 | 1.9 | p = 0.0087 |
Parameter | U87-WT Tumor | U87-mIDH Tumor | Significance |
---|---|---|---|
K1 (mL/ccm/min) | 0.174 ± 0.068 | 0.141 ± 0.047 | p = 0.401 |
k2 (1/min) | 0.553 ± 0.238 | 0.578 ± 0.173 | p = 0.858 |
k3 (1/min) | 0.089 ± 0.059 | 0.057 ± 0.040 | p = 0.343 |
k4 (1/min) | 0.044 ± 0.022 | 0.053 ± 0.023 | p = 0.525 |
VS (mL/ccm) | 0.576 ± 0.143 | 0.225 ± 0.070 | p = 0.001 |
VT (mL/ccm) | 0.921 ± 0.250 | 0.471 ± 0.084 | p = 0.005 |
K1/k2 (mL/ccm) | 0.345 ± 0.172 | 0.246 ± 0.063 | p = 0.261 |
k3/k4, BPND (1/1) | 1.874 ± 0.653 | 0.962 ± 0.399 | p = 0.029 |
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Cologni, R.; Holschbach, M.; Schneider, D.; Bier, D.; Schulze, A.; Stegmayr, C.; Endepols, H.; Ermert, J.; Neumaier, F.; Neumaier, B. Preparation and Preclinical Evaluation of 18F-Labeled Olutasidenib Derivatives for Non-Invasive Detection of Mutated Isocitrate Dehydrogenase 1 (mIDH1). Molecules 2024, 29, 3939. https://doi.org/10.3390/molecules29163939
Cologni R, Holschbach M, Schneider D, Bier D, Schulze A, Stegmayr C, Endepols H, Ermert J, Neumaier F, Neumaier B. Preparation and Preclinical Evaluation of 18F-Labeled Olutasidenib Derivatives for Non-Invasive Detection of Mutated Isocitrate Dehydrogenase 1 (mIDH1). Molecules. 2024; 29(16):3939. https://doi.org/10.3390/molecules29163939
Chicago/Turabian StyleCologni, Roberta, Marcus Holschbach, Daniela Schneider, Dirk Bier, Annette Schulze, Carina Stegmayr, Heike Endepols, Johannes Ermert, Felix Neumaier, and Bernd Neumaier. 2024. "Preparation and Preclinical Evaluation of 18F-Labeled Olutasidenib Derivatives for Non-Invasive Detection of Mutated Isocitrate Dehydrogenase 1 (mIDH1)" Molecules 29, no. 16: 3939. https://doi.org/10.3390/molecules29163939