AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (positive allosteric modulator). No IC50, Ki, EC50, or DC50 values are reported in this paper.

Middle-aged animals were more significantly enhanced by S 18986 in terms of memory than were older animals. In a model of spatial memory, middle-aged rodents with S 18986 show anti-amnestic characteristics [1]. Intraperitoneally administered S 18986 (5–50 mg/kg) dramatically enhances the onset and maintenance of 4 and 20 tetanus-induced potentiation [1].

Animal/Disease Models: Middle-aged (14-15 months old) mice [1]
Doses: 0.3, 1 and 10 mg/kg
Route of Administration: Oral
Experimental Results: Demonstrated anti-amnestic properties in middle-aged rodents.

---

In situ brain perfusion: Rats were anesthetized with diazepam (7.5 mg/kg i.p.) and ketamine (70 mg/kg i.p.). The right common carotid was catheterized; external carotid and occipital arteries were ligated. Perfusion fluid (bicarbonate-buffered physiological saline, pH 7.4, 37°C) containing [14C]S18986 at concentrations of 1.23, 6.14, or 12.27 μM, co-perfused with [3H]sucrose as vascular marker, was infused at 10 ml/min for 60 s. Perfusion was terminated by decapitation; brain was dissected into hippocampus, frontal cortex, and rest of brain; tissues were weighed, digested, and counted for dual-label radioactivity. (REF Materials and Methods, In Situ Brain Perfusion Technique)
Brain tissue and CSF pharmacokinetics: A water suspension of S18986 (1 mg/kg) was administered orally. At 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 min post-dose, CSF (50-100 µl) was collected by cisterna magna puncture under anesthesia (diazepam 7.5 mg/kg + ketamine 70 mg/kg i.p.), then rats were decapitated. Brain was dissected into frontal cortex, hippocampus, and rest. Three rats per time point. Samples stored at -20°C until HPLC-MS analysis. (REF Brain Tissue and CSF Pharmacokinetics)
Microdialysis for bECF and blood sampling: Rats were anesthetized with diazepam (7.5 mg/kg i.p.) and ketamine (70 mg/kg i.p.); right femoral vein was cannulated for blood collection. A guide cannula was implanted into frontal cortex (FC) or dorsal hippocampus (DH). After 24 h recovery, a microdialysis probe was inserted and perfused with brain physiological fluid at 2.3 µl/min for 2 h equilibration. Then S18986 was given orally at 1 mg/kg. Dialysates were collected every 30 min up to 3 h, then every hour from 3 to 5 h. Blood samples (180 µl) collected at 0, 5, 8, 15, 30, 60, 90, 120, 150, 180, 240, 300 min post-dose. Plasma obtained by centrifugation. Probe placement verified by microscopy. In vivo recovery of microdialysis probes was determined by retrodialysis using [14C]S18986; recovery was measured at end of experiment by perfusing 0.3 µM [14C]S18986 and collecting dialysates every 20 min for 2 h; recovery calculated as (Cin - Cout)/Cin. bECF concentrations were corrected by individual recovery. (REF bECF and Blood Pharmacokinetics, In Vivo Microdialysis Probe Recovery)

Plasma pharmacokinetics: After oral administration at 1 mg/kg, S18986 reached Cmax at Tmax = 8 min. Terminal half-life (t1/2) in plasma was about 1 h (60 min). Apparent total clearance (Cl/F) = 12.6 ml/min; apparent volume of distribution (Vd/F) = 998 ml; AUC0-∞ for total plasma = 4258 ng·ml⁻¹·min; for unbound plasma = 9986 ng·ml⁻¹·min (based on free fraction 32.9%). (REF Table 2, Fig. 4)
Brain pharmacokinetics: In frontal cortex (FC) and dorsal hippocampus (DH), terminal half-lives in CSF, bECF, and bICF were similar to plasma (~1 h). AUC ratios (brain compartment to unbound plasma AUC): bECF/plasma = 0.24 (FC) and 0.25 (DH); CSF/plasma = 0.4; bICF/plasma = 1 (FC) and 1.5 (DH). bICF/bECF AUC ratios = 4 (FC) and 6.2 (DH). (REF Table 2, Fig. 5)
BBB uptake clearance (Clup) measured by in situ brain perfusion was about 20 µl·s⁻¹·g⁻¹, independent of concentration (1.23-12.27 µM) and brain region (hippocampus, frontal cortex, rest of brain). Brain extraction coefficient relative to diazepam was ~45%. (REF Results, In Situ Brain Perfusion, Fig. 3)
Pharmacokinetic modeling: A multi-compartment model with first-order rate constants was fitted to plasma, CSF, bECF, and bICF data. The model assumed first-order absorption (Ka) and elimination (K10). Parameters estimated: Ka ≈ 0.15 min⁻¹, K10 ≈ 0.012-0.013 min⁻¹, V1/F ≈ 141-159 ml, Cl/F ≈ 15.7 ml/min. The model predicted concentrations that fitted observed data well, with parallel declines in all compartments. (REF Pharmacokinetic Modeling, Table 1)

Unbound plasma fraction: In vitro and in vivo experiments showed that the free plasma fraction was independent of S18986 concentrations, constant over time, and equal to 32.9 ± 4.8% in vivo (unpublished data from Institut de Recherches Internationales Servier). (REF Pharmacokinetic Analysis)

[1]. DRUG FOCUS: S 18986: A positive allosteric modulator of AMPA-type glutamate receptorspharmacological profile of a novel cognitive enhancer. CNS Neurosci Ther. 2010 Oct;16(5):e193-212.

[2]. Neuropharmacokinetics of a new alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) modulator, S18986 [(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide] in the rat. Drug Metab Dispos. 2005 Aug;33(8):113.

S18986 is a new pyrrolo-benzothiadiazine derivative (Desos et al., 1996). It is a positive allosteric modulator of AMPA receptors, enhancing cognitive functions in rodents. The compound activates the release of noradrenaline and acetylcholine in rat hippocampus (Lockhart et al., 2000; Rosi et al., 2004) and enhances memory in object-recognition tests (Lebrun et al., 2000). The study demonstrates that despite a bECF/unbound plasma AUC ratio below 1, the BBB uptake is high (Clup ~20 µl·s⁻¹·g⁻¹), which is explained by extensive partitioning into brain intracellular fluid (bICF), particularly in hippocampus. This highlights the importance of considering bECF/bICF partitioning when interpreting neuropharmacokinetics. (REF Introduction, Discussion)

C10H12N2O2S

224.278

224.062

175340-20-2

637863

White to light yellow solid powder

2.379

1

4

0

15

349

1

C1=CC=C2C(=C1)N3CCC[C@@H]3NS2(=O)=O

MNTIJYGEITVWHU-SNVBAGLBSA-N

InChI=1S/C10H12N2O2S/c13-15(14)9-5-2-1-4-8(9)12-7-3-6-10(12)11-15/h1-2,4-5,10-11H,3,6-7H2/t10-/m1/s1

(3aS)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide

S-18986S18986 S 18986 S 18986-1S18986-1 S-18986-1

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~445.87 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)