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| Targets |
FAP (fibroblast activation protein)
NOTA-FAPI-4 targets fibroblast activation protein (FAP), a serine protease that is selectively overexpressed in cancer-associated fibroblasts (CAFs) within the tumor microenvironment. It functions as a FAP inhibitor (blocker/antagonist). The NOTA chelator allows the compound to chelate radioactive metal ions such as ⁶⁸Ga, ⁶⁴Cu, or ¹⁸F (via ¹⁸F-AlF), enabling its use as a PET tracer for the non-invasive imaging of FAP-associated pathological conditions. |
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| ln Vitro |
The radiolabelling yield of Al18F-NOTA-FAPI was 33.8 ± 3.2% using manual synthesis (n = 10), with a radiochemical purity over 99% and the specific activity of 9.3-55.5 MBq/nmol. [1]
In vitro, NOTA-FAPI-4 demonstrates a radiolabeling yield of 33.8±3.2% (n=10) with Al¹⁸F, achieving a radiochemical purity of >99% and a specific activity of 9.3-55.5 MBq/nmol. Its FAP-binding affinity supports its use as a PET tracer for detecting FAP-associated diseases. The compound's quinoline-based structure enables high-affinity binding to FAP. |
| ln Vivo |
In this study, a novel aluminium-[18F]fluoride (Al18F)-labelled 1,4,7‑triazacyclononane-N,N',N″-triacetic acid (NOTA)-conjugated fibroblast activation protein inhibitor (FAPI) probe, named Al18F-NOTA-FAPI, was developed for fibroblast activation protein (FAP)-targeted tumour imaging; it could deliver hundreds of millicuries of radioactivity using automated synthesis. The tumour detection efficacy of Al18F-NOTA-FAPI was further validated in both preclinical and clinical translational studies.
Results: The radiolabelling yield of Al18F-NOTA-FAPI was 33.8 ± 3.2% using manual synthesis (n = 10), with a radiochemical purity over 99% and the specific activity of 9.3-55.5 MBq/nmol. The whole body effective dose of Al18F-NOTA-FAPI was estimated to be 1.24E - 02 mSv/MBq, which was lower than several other FAPI probes (68Ga-FAPI-04, 68Ga-FAPI-46 and 68Ga-FAPI-74). In U87MG tumour-bearing mice, Al18F-NOTA-FAPI showed good tumour detection efficacy based on the results of micro PET/CT imaging and biodistribution studies. In an organ biodistribution study of patients, Al18F-NOTA-FAPI showed a lower SUVmean than 2-[18F]-fluoro-2-deoxy-D-glucose (2-[18F]FDG) in most organs, especially in the liver (1.1 ± 0.2 vs. 2.0 ± 0.9), brain (0.1 ± 0.0 vs. 5.9 ± 1.3), and bone marrow (0.9 ± 0.1 vs. 1.7 ± 0.4). Meanwhile, Al18F-NOTA-FAPI did not show extensive bone uptake, and was able to detect more lesions than 2-[18F]FDG in the PET/CT imaging of several patients. Conclusion: The Al18F-NOTA-FAPI probe was successfully fabricated and applied in fibroblast activation protein-targeted tumour PET/CT imaging, which showed excellent imaging quality and tumour detection efficacy in U87MG tumour-bearing mice as well as in cancer patients.[1] In vivo, Al¹⁸F-NOTA-FAPI has been evaluated in preclinical and clinical translational studies. In U87MG tumor-bearing mice, it demonstrated excellent tumor detection efficacy. The estimated effective dose for Al¹⁸F-NOTA-FAPI is 1.24E-02 mSv/MBq, which is lower than other FAPI probes. As a PET tracer, it enables the detection of diseases or disorders associated with FAP, including various types of cancers where FAP is upregulated. |
| Enzyme Assay |
The binding of NOTA-FAPI-4 to FAP is assessed using radioligand binding assays with recombinant FAP protein. Competitive binding experiments are performed to confirm target engagement. Radiolabeling efficiency and radiochemical purity are measured using radio-HPLC or TLC. Typical protocols involve incubating the radiolabeled compound with FAP-expressing cell membranes and measuring bound radioactivity.
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| Cell Assay |
The radiolabelling procedure of Al18F-NOTA-FAPI was optimized. Cell uptake and competitive binding assays were completed with the U87MG and A549 cell lines to evaluate the affinity and specificity of the Al18F-NOTA-FAPI probe. [1]
The cellular activity of NOTA-FAPI-4 is evaluated in FAP-expressing cancer-associated fibroblasts or cancer cell lines. Cells are incubated with radiolabeled NOTA-FAPI-4, and cellular uptake is measured. Binding specificity is confirmed by competition with unlabeled FAPI-4. Cellular uptake studies are typically performed at 37°C for various time points to determine binding kinetics. |
| Animal Protocol |
The biodistribution, pharmacokinetics, radiation dosimetry and tumour imaging efficacy of the Al18F-NOTA-FAPI probe were researched in healthy Kunming (KM) and/or U87MG model mice. After the approval of the ethical committee, the Al18F-NOTA-FAPI probe was translated into the clinic for PET/CT imaging of the first 10 cancer patients.
The biodistribution, pharmacokinetics, radiation dosimetry and tumour imaging efficacy of the Al18F-NOTA-FAPI probe were researched in healthy Kunming (KM) and/or U87MG model mice. After the approval of the ethical committee, the Al18F-NOTA-FAPI probe was translated into the clinic for PET/CT imaging of the first 10 cancer patients.[1]
In vivo studies of NOTA-FAPI-4 are conducted in tumor-bearing mouse models. Animals are administered radiolabeled NOTA-FAPI-4, and PET imaging is performed to assess tumor uptake and biodistribution. Tumor-to-background contrast ratios are calculated to evaluate imaging efficacy. Biodistribution studies involve dissecting tissues and measuring radioactivity to determine the compound's organ distribution. |
| ADME/Pharmacokinetics |
NOTA-FAPI-4 has a molecular formula of C36H47F2N9O8 and a molecular weight of 771.82. Its IUPAC name is (S)-2,2'-(7-(2-(4-(3-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazin-1-yl)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid. Purity is 98%. The compound is a solid powder that should be protected from light during transportation and storage. It is soluble in DMSO (~100 mg/mL). Storage conditions are powder at -20°C for up to 3 years or in solvent at -80°C for 6 months.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for NOTA-FAPI-4 are limited. The compound is intended for research use only and not for diagnostic or therapeutic use in humans. Standard laboratory safety precautions should be followed.
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| References | |
| Additional Infomation |
NOTA-FAPI-4 is a FAP-targeting PET tracer for non-invasive imaging of FAP-associated pathological conditions and monitoring of therapeutic responses. It can be used to diagnose or treat diseases characterized by FAP overexpression. As a ⁶⁸Ga-labeled PET tracer, it is applicable for early diagnosis of solid tumors such as pancreatic cancer and lung cancer. NOTA-FAPI-4 is also known as NOTA-FAPI-04 and NTFAPI.
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| Molecular Formula |
C36H47F2N9O8
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|---|---|
| Molecular Weight |
771.81
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| Exact Mass |
771.35
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| Elemental Analysis |
C, 56.02; H, 6.14; F, 4.92; N, 16.33; O, 16.58
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| CAS # |
2374782-03-1
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| Related CAS # |
2374782-03-1;
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| PubChem CID |
139400498
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
-4.2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
55
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| Complexity |
1380
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CN(CCN1CCCOC2=CC3=C(C=CN=C3C=C2)C(=O)NCC(=O)N4CC(C[C@H]4C#N)(F)F)C(=O)CN5CCN(CCN(CC5)CC(=O)O)CC(=O)O
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| InChi Key |
XQARGGQZFNOLDH-SANMLTNESA-N
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| InChi Code |
InChI=1S/C36H47F2N9O8/c37-36(38)19-26(20-39)47(25-36)31(48)21-41-35(54)28-4-5-40-30-3-2-27(18-29(28)30)55-17-1-6-42-13-15-46(16-14-42)32(49)22-43-7-9-44(23-33(50)51)11-12-45(10-8-43)24-34(52)53/h2-5,18,26H,1,6-17,19,21-25H2,(H,41,54)(H,50,51)(H,52,53)/t26-/m0/s1
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| Chemical Name |
(S)-2,2'-(7-(2-(4-(3-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazin-1-yl)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid
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| Synonyms |
NOTA-FAPI-4; NOTA-FAPI-04; NTFAPI; NTFAPI; NOTA-FAPI; 2374782-03-1; NOTA-FAPI-04; RD4ZKJ67G3; FAPI-42; (S)-2,2'-(7-(2-(4-(3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazin-1-yl)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid; 1H-1,4,7-Triazonine-1,4(5H)-diacetic acid, 7-(2-(4-(3-((4-(((2-((2S)-2-cyano-4,4-difluoro-1-pyrrolidinyl)-2-oxoethyl)amino)carbonyl)-6-quinolinyl)oxy)propyl)-1-piperazinyl)-2-oxoethyl)hexahydro-;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~129.57 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.24 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2957 mL | 6.4783 mL | 12.9566 mL | |
| 5 mM | 0.2591 mL | 1.2957 mL | 2.5913 mL | |
| 10 mM | 0.1296 mL | 0.6478 mL | 1.2957 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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