Structure of 769-39-1
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Batch number can be found on the product's label following the word 'Batch'.
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Kanellopoulos, Panagiotis ; Lundmark, Fanny ; Abouzayed, Ayman ; Balestri, Lorenzo Jacopo Ilic ; Håkansson, Esther Olaniran ; Obeid, Karim , et al.
Abstract: Background: The gastrin-releasing peptide receptor (GRPR) is overexpressed in the majority of primary prostate cancer lesions, with persistent expression in lymph nodes and bone metastases, making it a legitimate molecular target for diagnostic imaging and staging. This study presents the synthesis and preclinical evaluation of [18F]MeTz-PEG2-RM26, a GRPR antagonist which utilises the Inverse Electron Demand Diels-Alder (IEDDA) reaction for 18F-labelling. This click-chemistry approach allows for site-specific incorporation of fluorine-18 under mild conditions, preserving the peptide's structural integrity and biological activity. Receptor specificity and affinity of [18F]MeTz-PEG2-RM26 were evaluated in vitro using GRPR-expressing PC-3 cells. Furthermore, the biodistribution profile of [18F]MeTz-PEG2-RM26 was assessed in NMRI mice and its tumour-targeting capability was investigated in mice bearing PC-3 xenografts. Results: The labelling of TCO-PEG2-RM26 precursor involved three steps: (1) synthesis of an 18F-labelled activated ester on a quaternary methyl ammonium (QMA) cartridge, (2) conjugation of the labelled ester to a tetrazine amine, and (3) attachment to TCO-PEG2-RM26 via an IEDDA click reaction. This production method of [18F] MeTz-PEG2-RM26 afforded a high apparent molar activity of 3.5–4.3 GBq/µmol and radiochemical purity exceeding 98%, with 43–70 MBq activity incorporation, while the entire synthesis was completed within 75 min. Both in vitro and in vivo studies confirmed the specific binding of [18F]MeTz-PEG2-RM26 to GRPR, with a significant reduction in activity uptake observed upon receptor saturation. The radioligand exhibited rapid blood clearance and minimal bone uptake, confirming the stability of the fluorine-carbon bond. However, high hepatic uptake (12–13% IA/g at 1 h postinjection) indicated predominant hepatobiliary excretion. Receptor-mediated uptake was observed in the tumours and pancreatic tissue, although the overall activity uptake in tumours was low, likely due to the rapid hepatobiliary clearance of [18F] MeTz-PEG2-RM26. Conclusions: These findings demonstrate the effectiveness of the IEDDA click reaction for fluorine-18 labelling of GRPR-targeting PET tracers. Future studies should focus on increasing the hydrophilicity of the imaging probe to improve the targeting properties and biodistribution profile of the radioligand.
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Keywords: Fluorine-18 ; TCO ; Tetrazine ; IEDDA click chemistry ; GRPR ; Bombesin ; PET ; Prostate cancer
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CAS No. : | 769-39-1 |
Formula : | C6H2F4O |
M.W : | 166.07 |
SMILES Code : | OC1=C(F)C(F)=CC(F)=C1F |
MDL No. : | MFCD00002157 |
InChI Key : | PBYIIRLNRCVTMQ-UHFFFAOYSA-N |
Pubchem ID : | 69858 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 28.3 |
TPSA ? Topological Polar Surface Area: Calculated from |
20.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.47 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.07 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.63 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.21 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.08 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.69 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.58 |
Solubility | 0.439 mg/ml ; 0.00265 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.12 |
Solubility | 1.25 mg/ml ; 0.00752 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.93 |
Solubility | 0.195 mg/ml ; 0.00117 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.84 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.26 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20.0h; | General procedure: A mixture of 3 (1.87 g, 8 mmol) and 2,3,5,6-tetrafluorophenol (3.32 g, 20 mmol) in dichloromethane (40 mL) was added N,N’-dicyclohexylcarbodiimide (3.30 g, 16 mmol). The resulting solution was stirred at room temperature for 20 h, and filtered. The filtrate was washed with aqueous NaOH solution (1 N, 100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography with 15:85 diethyl ether/hexane to yield 5 as white solid (2.42 g, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N,N-dimethyl-aniline; at 160℃; for 5h; | Dissolve 210g of <strong>[652-34-6]4-hydroxy-2,3,5,6-tetrafluorobenzoic acid</strong> dry product in 1050g of N,N-dimethylaniline, slowly raise the temperature to reflux with stirring, and reflux for 5 hours at 160C. Sampling and HPLC analysis showed that the raw material <strong>[652-34-6]4-hydroxy-2,3,5,6-tetrafluorobenzoic acid</strong> was completely converted. The temperature was lowered. The reaction solution was poured into 5L cold water, extracted three times with dichloromethane, combined the extracts, and washed three times with water, dried over anhydrous magnesium sulfate, concentrated, distilled, and then rectified to obtain 147 g of 2,3,5,6-tetrafluorophenol with a yield of 88% and an HPLC content of 99.1%. |