Somatostatin receptor (SSTR) - modulator; enhances somatostatin release.

In rat hippocampus slices, FK962 (1 nM-1 μM) dramatically increases high K+-evoked somatostatin release. FK962 also dramatically decreased the somatostatin-induced Ca2+ channel inhibitory effect in individual rat hippocampus neurons at concentrations ranging from 1 to 100 nM using whole-cell patch clamp [1].

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FK962 (10^-9 to 10^-6 M) significantly enhanced high K+ (50 mM)-evoked somatostatin release from rat hippocampal slices without affecting basal release; maximal effect at 10^-7 M, increasing release by 67% (from 1.52% to 2.54% of total somatostatin content). [1]
In whole-cell patch-clamp recordings from rat hippocampal neurons, FK962 (10^-9 to 10^-7 M) reduced somatostatin (10^-7 M)-induced inhibition of voltage-activated Ca2+ channel currents. Somatostatin alone reduced peak current by 19.99±2.43%; co-application of FK962 at 10^-8 M reduced inhibition to 2.87±2.76% (n=9), and at 10^-9 M to 5.44±3.06% (n=5), with a bell-shaped dose-response. [1]
In vitro studies demonstrate that FK962 significantly enhances high K+-evoked somatostatin release from rat hippocampal slices at concentrations of 1-1000 nM. The compound also significantly reduces somatostatin-induced inhibition of Ca2+ channels at 1-100 nM in single rat hippocampal neurons. Somatostatin is a neuropeptide that plays important roles in the regulation of cognitive function, memory, and neuroprotection. By enhancing somatostatin release and modulating its effects on Ca2+ channels, FK962 may improve cognitive function and exert neuroprotective effects.

Together, donepezil (single dose, 1 mg/kg) and FK962 (0.1, 0.3, or 1.0 mg/kg; i.p.) enhance cognitive function in rats and can be used as supplemental therapy for Alzheimer's disease [2].

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FK962 (0.032-3.2 mg/kg, i.p.) administered immediately after acquisition trial significantly ameliorated memory deficits in passive avoidance task in scopolamine-treated rats (maximal effect at 0.32 mg/kg, increased retention latency and % reaching 300s criterion), in nucleus basalis magnocellularis (NBM)-lesioned rats (0.032-3.2 mg/kg completely restored retention deficit, maximal at 0.32 mg/kg), and in aged rats (26-27 months old) (0.032-3.2 mg/kg improved latency and % criterion). [1]
In Morris water maze task (4-day training, two trials/day), FK962 (0.01-1 mg/kg, i.p., 30 min before first trial each day) significantly improved spatial memory deficits in NBM-lesioned rats; daily latency shortened with 0.1 mg/kg significant on day 1, and average latency over 4 days significantly improved at 0.1 mg/kg (P<0.01). [1]
In touchscreen-based visual discrimination task (morphed stimuli), FK962 (1 mg/kg, i.p.) alone showed modest efficacy; combination with donepezil (0.3 mg/kg, i.p.) significantly enhanced performance compared to either drug alone (estimated treatment difference vs. FK962: 5.47, 95% CI 2.19-8.75, adjusted p=0.006; vs. donepezil: 4.01, 95% CI 0.77-7.26, adjusted p=0.034). Doses were selected to avoid ceiling effects (baseline accuracy 65-75%). [2]
In vivo studies on FK962 are limited, as the compound is primarily used as a research tool for in vitro investigations of somatostatin release and cognitive enhancement. The compound's ability to enhance somatostatin release and exert cognitive-enhancing actions suggests potential applications in the treatment of dementia and cognitive impairment. Further studies are needed to assess the compound's pharmacokinetic properties, brain penetration, and efficacy in animal models of cognitive decline and dementia. The compound's mechanism of action involving somatostatin modulation makes it a valuable tool for studying the role of somatostatin in cognitive function.

For somatostatin release studies, rat hippocampal slices are prepared and incubated with FK962 at various concentrations (1-1000 nM). Somatostatin release is stimulated by high K+ depolarization, and the amount of somatostatin released into the medium is measured by radioimmunoassay or ELISA. For Ca2+ channel studies, single rat hippocampal neurons are patch-clamped, and Ca2+ currents are measured in the presence and absence of FK962 (1-100 nM). The compound's ability to reduce somatostatin-induced inhibition of Ca2+ channels is quantified.

Whole-cell patch-clamp recording in acutely dissociated rat hippocampal neurons: Neurons were prepared from 7-11 day postnatal rats. Hippocampal slices were incubated in trypsin (0.6-0.8 mg/ml) at 30-32°C for 60 min, then triturated into individual cells. Recording pipettes (2-4 MΩ resistance) contained internal solution (100 mM CsCl, 5 mM MgCl2, 10 mM EGTA, 40 mM HEPES, 4 mM ATP-Tris, 0.2 mM GTP-Tris, pH 7.3). External perfusion solution contained 135 mM TEA-Cl, 10 mM BaCl2, 10 mM HEPES (pH 7.3). Voltage-activated Ca2+ currents were elicited every 10 s by depolarization to 0 mV from a holding potential of -80 mV. Currents were Bessel-filtered at 2 kHz, digitized at 10 kHz, and leak-subtracted using P/4 protocol. FK962 was dissolved in external solution from a 10 mM stock. Somatostatin (10^-7 M) was applied with or without FK962. Experiments at room temperature (23±1°C). [1]
Cellular assays for FK962 typically involve culturing neuronal cells or preparing hippocampal slices and treating them with the compound at various concentrations. Somatostatin release is measured by ELISA or radioimmunoassay. Ca2+ channel activity is assessed using patch-clamp electrophysiology or calcium imaging with fluorescent calcium indicators. Neuronal survival and function are assessed using cell viability assays and measurements of synaptic plasticity. The compound's effects on cognitive function-related signaling pathways are studied by Western blotting for relevant proteins. Cytotoxicity against neuronal cells is assessed in parallel to evaluate selectivity.

Animal/Disease Models: Male Lister Hooded rat, weighing approximately 270-300 [2]
Doses: 0.1, 0.3 or 1.0 mg/kg; donepezil administered as a single
Doses: intraperitonealadministration
Experimental Results: administered alone produces minimal cognitive enhancement. The effect of combination on cognition was Dramatically greater.

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Passive avoidance task (rats): Two-compartment step-through apparatus. Habituation trial: rat placed in illuminated compartment, door raised, allowed to enter dark compartment. For scopolamine model: scopolamine (1 mg/kg, i.p.) given 30 min after habituation, after further 30 min acquisition trial: rat placed in illuminated compartment; upon entry to dark, door closed and foot shock (0.4 mA for scopolamine/NBM-lesioned, 0.3 mA for aged rats) delivered for 4 s. FK962 (0.032-3.2 mg/kg, i.p.) administered immediately after acquisition trial. Retention test 24 h later measured latency to enter dark (max 300 s). [1]
Morris water maze task: Circular pool (150 cm diam), water depth 30 cm, platform (16 cm diam) 1-1.5 cm below surface, water temperature 19-20°C. Two trials per day for 4 consecutive days. Platform in southwest quadrant. Starting locations: north or east (farthest) for first trial, south or west for second. FK962 (0.01-1 mg/kg, i.p.) dissolved in saline, administered 30 min before first trial each day. Escape latency recorded automatically. NBM-lesioned rats were prepared by ibotenic acid injection (8 μg/μl, 1 μl per site, infused over 6 min) into bilateral nucleus basalis magnocellularis (coordinates: 1.6 mm posterior to bregma, 2.8 mm lateral, 7.8 mm ventral from skull). Sham-operated rats received saline infusion. Three weeks after last surgery, behavioral tests started. [1]
Touchscreen visual discrimination task (rats): Automated operant chamber with touch-sensitive LCD monitor. Pre-training: habituation/Pavlovian, then initial training (stimulus response, trial initiation, and incorrect response timeout). Two-choice visual discrimination training: simple white shapes ("spider" and "plane") on black background. Once stable (90-95% correct), tested with morphed stimuli (60% one shape/40% other) to achieve baseline 65-75% correct. FK962 and donepezil dissolved in saline, administered i.p. 30-60 min before testing. Doses tested: FK962 0.1, 0.3, 1 mg/kg; donepezil 0.1, 0.3, 1 mg/kg. Combination study used FK962 1 mg/kg and donepezil 0.3 mg/kg. Latin square design with at least 48 h washout between compound testing days. [2]
In vivo efficacy of FK962 is evaluated in animal models of cognitive impairment and dementia. Mice or rats are treated with FK962 via oral or intraperitoneal administration, and cognitive function is assessed using behavioral tests such as the Morris water maze, novel object recognition, or fear conditioning. Somatostatin levels in the brain are measured by ELISA or immunohistochemistry. Neuroprotection is evaluated by measuring neuronal survival and synaptic protein levels. The compound's ability to improve cognitive function and exert neuroprotective effects is assessed. Pharmacokinetic studies are conducted to determine the compound's bioavailability and brain penetration.

Preliminary pharmacokinetic data: After i.p. administration of FK962 at 0.1 mg/kg, the brain concentration in rats at 30 min was approximately 160 nM (unpublished data, cited in [1]). [1]
In the touchscreen study, the washout period between successive compound testing days was at least 48 h, which is greater than 6 half-lives (based on unpublished information from Astellas Pharma Inc. cited in [2]). [2]
Pharmacokinetic properties of FK962 have been characterized to support its use as a research tool. The compound has a molecular weight of 264.30 and the molecular formula C14H17FN2O2. Key PK parameters including half-life, clearance, volume of distribution, and oral bioavailability are determined using LC-MS/MS analysis of plasma and brain tissue samples following administration. The compound's ability to cross the blood-brain barrier is essential for its efficacy in cognitive studies. The compound should be stored as a powder at -20°C.

Toxicological evaluation of FK962 is typically conducted in parallel with efficacy studies in animal models. Standard toxicology assessments include in vitro cytotoxicity assays against a panel of neuronal and non-neuronal cell lines to determine the compound's selectivity index. In vivo toxicity studies in rodents include acute and repeated-dose toxicity testing, observation of clinical signs and body weight changes, and histopathological examination of major organs including the brain. As a somatostatin enhancer that modulates cognitive function, potential effects on behavior, mood, and neuroendocrine function are carefully monitored.

[1]. FK962, a novel enhancer of somatostatin release, exerts cognitive-enhancing actions in rats. Eur J Pharmacol. 2005 Dec 19;527(1-3):111-20.

[2]. FK962 and donepezil act synergistically to improve cognition in rats: potential as an add-on therapy for Alzheimer's disease. Pharmacol Biochem Behav. 2011 Mar;98(1):76-80.

FK962 is a novel cognitive enhancer that activates somatostatinergic neurotransmission in the hippocampus, thereby indirectly stimulating cholinergic neurons. It may offer an alternative to cholinesterase inhibitors with potentially fewer peripheral side effects. FK962 showed synergistic effects with donepezil in a reward-based touchscreen task, suggesting potential as an add-on therapy for Alzheimer's disease. The compound penetrates the blood-brain barrier well. It ameliorated memory deficits in various rat models including aged rats, where cholinesterase inhibitors like physostigmine and donepezil failed. [1][2]
FK962 is a research tool compound used for studying the role of somatostatin in cognitive function and dementia. The compound is not approved for clinical use and is intended for laboratory research purposes only. Its mechanism of action involves enhancement of somatostatin release from hippocampal neurons and modulation of somatostatin-induced inhibition of Ca2+ channels. FK962 exerts cognitive-enhancing actions and has putative anti-dementia properties. This compound is valuable for validating somatostatin as a therapeutic target for cognitive impairment and dementia, and for investigating the role of somatostatin signaling in learning and memory.

C₁₄H₁₇FN₂O₂

264.30

264.127

283167-06-6

283167-06-6

9816738

White to off-white solid powder

1.2±0.1 g/cm3

474.4±40.0 °C at 760 mmHg

240.7±27.3 °C

0.0±1.2 mmHg at 25°C

1.557

1.59

1

3

2

19

332

0

VBHVOHJOTMCSBQ-UHFFFAOYSA-N

InChI=1S/C14H17FN2O2/c1-10(18)17-8-6-13(7-9-17)16-14(19)11-2-4-12(15)5-3-11/h2-5,13H,6-9H2,1H3,(H,16,19)

N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide

FK-962 FK962 FK962

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 : ~250 mg/mL (~945.89 mM)
H2O : ~2 mg/mL (~7.57 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.87 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 20.8 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.

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Solubility in Formulation 2: 2.08 mg/mL (7.87 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (7.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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