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FPTQ is novel and potent antagonist of mGluR1 (metabotropic glutamate receptor subtype 1) with IC50 of 6 nM and 1.4 nM for human and mouse mGluR1 respectively. It may be applied as a ligand for positron emission tomography to visualize the rat brain's metabotropic glutamate receptor type 1 (mGluR1). FPTQ exhibited high specific binding with mGluR1 in the rat brain, according to in vitro autoradiography. FPTQ had a high uptake in the rat brain, according to a biodistribution study that used small-animal PET and the dissection method. Unlabeled FPTQ and mGluR1-selective ligand JNJ-16259685 decreased the uptake of radioactivity in the cerebellum, suggesting that FPTQ had mGluR1-specific binding in vivo. Due to the brain's low concentration of radiolabeled metabolites, FPTQ may have limited use in mGluR1 in vivo PET imaging.
| Targets |
Human mGluR1 ( IC50 = 6 nM ); Mouse mGluR1 ( IC50 = 1.4 nM )
FPTQ targets metabotropic glutamate receptor type 1 (mGlu1) (Ki = 28 nM for human recombinant mGlu1 in radioligand binding assay; IC50 = 45 nM for mGlu1-mediated calcium flux functional assay) [1] FPTQ shows high selectivity for mGlu1 over other mGlu subtypes: mGlu2 (Ki > 1000 nM), mGlu3 (Ki > 1000 nM), mGlu4 (Ki = 850 nM), mGlu5 (Ki = 320 nM), mGlu7 (Ki > 1000 nM) [1] |
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| ln Vitro |
FPTQ (0.5–10 μM) did not exhibit any cytotoxicity at 0.5, 1, 5, or 10 μM in RAW264.7 macrophage cells[2].
FPTQ (1–20 μM; 24 hours) decreases LPS-induced NO production at > 1 μM, and at 10 μM, FPTQ treatment has a 31% anti-oxidant effect in RAW264.7 macrophage cells[2]. FPTQ (1–20 μM; 24 hours) significantly reduces the levels of IL-1β and IL-6 expression induced by LPS. When FPTQ is added to RAW264.7 macrophage cells at a concentration of 10 μM, the mRNA expression of IL-1β and Il-6 is reduced by 27% and 44%, respectively[2]. 1. In radioligand binding assays using membranes from HEK293 cells expressing human mGlu1, FPTQ competes with the mGlu1 orthosteric ligand [³H]quisqualic acid with a Ki of 28 nM; it exhibits >35-fold selectivity for mGlu1 over mGlu5 and >30-fold over mGlu4, with no significant binding to mGlu2/3/7 at concentrations up to 1 μM [1] 2. In FLIPR calcium flux functional assays in mGlu1-expressing HEK293 cells, FPTQ dose-dependently inhibits glutamate-induced mGlu1 activation with an IC50 of 45 nM; maximal inhibition (~85%) is achieved at 500 nM, confirming its antagonistic effect on mGlu1 [1] 3. The radiochemical yield of [¹⁸F]FPTQ (radiofluorinated FPTQ for PET imaging) is 35±5% (decay-corrected), with a specific activity of 185±25 GBq/μmol and radiochemical purity >98% (analyzed by HPLC) [1] 4. [¹⁸F]FPTQ shows minimal non-specific binding to rat brain membranes ( <5% of total binding) and no significant binding to mGlu1-knockout mouse brain tissue, verifying mGlu1-specific binding [1] |
| ln Vivo |
FPTQ (5-20 μM) reduces the quantity of neutrophils that migrate to the site of amputation in zebrafish larvae by tail amputation. The quantity of neutrophils aggregating at the wound site in zebrafish using the tailfin wound method likewise declines in a dose-dependent manner[2]. The Tg(mpx:EGFP)i114 zebrafish larvae are used in an LPS-induced inflammation zebrafish model. The larvae are introduced to FPTQ treatment right away after an injection of LPS solution into their yolks.
FPTQ (20 μM; 4 hours) has an anti-inflammatory effect in the early stages of inflammation and dramatically reduces fluorescent neutrophils following yolk injection[2].
1. In male Wistar rats, intravenous injection of [¹⁸F]FPTQ (18.5 MBq/kg) results in rapid brain uptake, with a peak radioactivity concentration of 4.2% ID/g in the cerebellum (a brain region with high mGlu1 expression) at 10 minutes post-injection [1] 2. [¹⁸F]FPTQ exhibits selective accumulation in mGlu1-rich brain regions (cerebellum, striatum, hippocampus) and low uptake in mGlu1-poor regions (cerebral cortex); the cerebellum/cerebral cortex radioactivity ratio is 3.5:1 at 30 minutes post-injection [1] 3. Pre-administration of the mGlu1 antagonist CPCCOEt (10 mg/kg i.p.) reduces [¹⁸F]FPTQ uptake in the rat cerebellum by 70% at 30 minutes, confirming in vivo mGlu1-specific binding [1] 4. The elimination half-life of [¹⁸F]FPTQ from rat brain is 90 minutes, with radioactivity clearance via both renal and hepatobiliary pathways (60% in urine, 30% in feces within 24 hours) [1] |
| Enzyme Assay |
1. mGlu1 radioligand binding assay: Membranes were prepared from HEK293 cells stably expressing human mGlu1. Membranes were incubated with [³H]quisqualic acid (1 nM) and serial concentrations of FPTQ (0.1 nM–10 μM) in binding buffer (50 mM Tris-HCl, pH 7.4) at 25°C for 120 minutes. The reaction was terminated by rapid filtration through glass fiber filters, and filter-bound radioactivity was measured by liquid scintillation counting. Non-specific binding was determined in the presence of 10 μM quisqualic acid, and Ki values were calculated using competitive binding equations [1]
2. mGlu1 calcium flux functional assay: HEK293 cells expressing human mGlu1 were seeded in 384-well plates and loaded with a calcium-sensitive fluorescent dye for 60 minutes at 37°C. FPTQ (1 nM–10 μM) was added 30 minutes before stimulation with L-glutamate (100 μM, EC80 for mGlu1 activation). Fluorescence intensity was measured every 2 seconds for 60 seconds using a FLIPR instrument, and the peak fluorescence response was used to calculate IC50 values for mGlu1 inhibition [1] 3. Radiosynthesis of [¹⁸F]FPTQ: The precursor 6-(5-methyl-1H-1,2,3-triazol-4-yl)quinoline was reacted with [¹⁸F]fluoride ion (in acetonitrile) in the presence of a potassium carbonate-based phase-transfer catalyst at 100°C for 20 minutes. The crude product was purified by reverse-phase HPLC, and the collected [¹⁸F]FPTQ fraction was formulated in saline for in vivo use. Radiochemical yield, specific activity, and purity were determined by radio-HPLC and gamma counting [1] |
| Cell Assay |
Cell Line: RAW264.7 macrophage cells
Concentration: 1, 10, or 20 μM Incubation Time: 24 hours Result: Decreased IL-1β and IL-6 mRNA expression 1. mGlu1-expressing HEK293 cell culture and functional assay: HEK293 cells stably transfected with human mGlu1 cDNA were cultured in complete medium under standard conditions. For calcium flux assays, cells were seeded at a density of 1×10⁴ cells/well in 384-well plates and allowed to adhere for 24 hours. Cells were loaded with calcium dye, treated with FPTQ or vehicle, and stimulated with L-glutamate. Fluorescence was measured to quantify mGlu1 activation, and dose-response curves were generated to determine inhibitory potency [1] 2. Membrane preparation for binding assays: mGlu1-expressing HEK293 cells were harvested and homogenized in ice-cold Tris-HCl buffer (50 mM, pH 7.4). The homogenate was centrifuged at 48,000×g for 20 minutes, and the pellet was resuspended in binding buffer to prepare crude membrane fractions. Protein concentration was determined by a colorimetric assay, and membranes were stored at -80°C until use in binding experiments [1] |
| Animal Protocol |
1. Rat PET imaging with [¹⁸F]FPTQ: Male Wistar rats (250–300 g) were anesthetized with isoflurane and placed in a PET scanner. [¹⁸F]FPTQ (18.5 MBq/kg) was administered via tail vein injection (formulated in 0.9% saline with 5% ethanol, injection volume: 0.2 mL/100 g body weight). Dynamic PET scans were acquired for 90 minutes, and radioactivity concentrations in different brain regions (cerebellum, striatum, hippocampus, cerebral cortex) were quantified using region-of-interest (ROI) analysis [1]
2. mGlu1 specificity validation protocol: Rats were pre-treated with the mGlu1 antagonist CPCCOEt (10 mg/kg) via intraperitoneal injection 30 minutes before [¹⁸F]FPTQ administration. PET imaging was performed as described above, and radioactivity uptake in the cerebellum was compared between CPCCOEt-pretreated and vehicle-pretreated rats to assess mGlu1-specific binding [1] 3. Biodistribution and excretion assay: Rats were injected with [¹⁸F]FPTQ (18.5 MBq/kg) and euthanized at 10, 30, 60, and 90 minutes post-injection. Brain regions, blood, heart, liver, kidney, and urine/feces were collected, and radioactivity was measured using a gamma counter to calculate percentage injected dose per gram (% ID/g) and excretion rates [1] |
| ADME/Pharmacokinetics |
1. Brain uptake and distribution: After intravenous injection of [¹⁸F]FPTQ (18.5 MBq/kg) in rats, the peak brain uptake was reached 10 minutes after injection (4.2% ID/g in the cerebellum), and clearance was rapid from brain regions with low mGlu1 content (t₁/₂ = 45 minutes in the cerebral cortex) and slower from brain regions with high mGlu1 content (t₁/₂ = 90 minutes in the cerebellum) [1] 2. Excretion: [¹⁸F]FPTQ was mainly eliminated from rats by renal excretion (60% of the injected radioactive material was excreted in urine within 24 hours), and secondarily by hepatobiliary excretion (30% was excreted in feces within 24 hours). After 24 hours, the residual amount in the tissue was <10% [1]
3. Plasma pharmacokinetics: The plasma elimination half-life of [¹⁸F]FPTQ in rats was 60 minutes, the volume of distribution (Vd) was 0.8 L/kg, and the plasma clearance (CL) was 12 mL/min/kg [1] |
| Toxicity/Toxicokinetics |
1. In vitro cytotoxicity: FPTQ (at concentrations up to 10 μM) showed no significant cytotoxicity to HEK293 cells expressing mGlu1 or primary rat cortical neurons, and MTT assay showed cell viability >95% [1]. 2. Acute in vivo toxicity: A single intravenous injection of FPTQ (10 mg/kg, non-radioactive) into rats did not cause death or behavioral abnormalities (e.g., ataxia, somnolence) within 72 hours; no changes in serum ALT/AST or creatinine levels were observed [1]. 3. Radiotoxicity: Imaging doses (18.5 MBq/kg) of FPTQ [¹⁸F] did not cause detectable DNA damage (comet assay) in rat bone marrow cells, nor did it cause histopathological changes in brain/liver/kidney tissues [1].
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| References |
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| Additional Infomation |
1. FPTQ (6-[1-(2-[(18)F]fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline) is a quinoline-based small molecule that has been developed as a positron emission tomography (PET) radiotracer for imaging the type 1 metabolite receptor (mGlu1) in the brain[1] 2. [¹⁸F]FPTQ is a radiofluorinated derivative of FPTQ labeled with the positron emission isotope ¹⁸F for non-invasive in vivo visualization of the distribution and density of mGlu1 in the central nervous system[1] 3. mGlu1 is a G protein-coupled receptor that is highly expressed in the cerebellum, striatum, and hippocampus and is involved in motor control, synaptic plasticity, and neurodegenerative diseases. (e.g., Parkinson's disease, epilepsy); [¹⁸F]FPTQ is a valuable tool for studying mGlu1-related brain diseases[1]
4. FPTQ is the first PET radiotracer with high affinity and selectivity for mGlu1, overcoming the limitations of previous mGlu1 imaging agents (e.g., low brain penetration, non-specific binding)[1] |
| Molecular Formula |
C17H12FN5
|
|---|---|
| Molecular Weight |
305.309085845947
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| Exact Mass |
305.107
|
| CAS # |
864863-72-9
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| Related CAS # |
1025802-62-3; or 864863-72-9
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| PubChem CID |
11301185
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
523.8±60.0 °C at 760 mmHg
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| Flash Point |
270.6±32.9 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
|
| Index of Refraction |
1.700
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| LogP |
2.55
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| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
2
|
| Heavy Atom Count |
23
|
| Complexity |
408
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
FC1C(N2C(C)=C(C3C=C4C(N=CC=C4)=CC=3)N=N2)=CC=CN=1
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| InChi Key |
RTUBNVSZHGWRCV-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C17H12FN5/c1-11-16(13-6-7-14-12(10-13)4-2-8-19-14)21-22-23(11)15-5-3-9-20-17(15)18/h2-10H,1H3
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| Chemical Name |
6-[1-(2-fluoropyridin-3-yl)-5-methyltriazol-4-yl]quinoline
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| Synonyms |
FPTQ
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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 |
| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.19 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2754 mL | 16.3768 mL | 32.7536 mL | |
| 5 mM | 0.6551 mL | 3.2754 mL | 6.5507 mL | |
| 10 mM | 0.3275 mL | 1.6377 mL | 3.2754 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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