Mardepodect (PF-2545920; MP-10) is a selective inhibitor of phosphodiesterase 10A (PDE10A). It exhibits high affinity for human recombinant PDE10A with a Ki value of 0.39 nM (measured using cAMP as substrate) and 0.47 nM (using cGMP as substrate). It shows excellent selectivity over other PDE isoforms (PDE1-PDE9, PDE11), with inhibition of these isoforms being negligible (IC50 > 10,000 nM for all tested non-PDE10A isoforms). [1]
- Mardepodect (PF-2545920; MP-10) specifically targets PDE10A in the central nervous system (CNS), with no significant binding to other CNS receptors (e.g., dopamine D2, serotonin 5-HT2A, glutamate NMDA receptors) or enzymes (e.g., monoamine oxidase A/B) at therapeutic concentrations. [2]

PF-2545920（也称为 Mardepodect、MP-10）是一种有效的选择性 PDE10A（磷酸二酯酶）抑制剂，IC50 为 0.37 nM，选择性是 PDE 的 1000 倍以上。它对于治疗精神分裂症有潜在的用途。 PF-2545920 在一系列抗精神病模型中具有活性，可拮抗阿扑吗啡诱导的小鼠攀爬，抑制大鼠和小鼠的条件性回避反应，并阻断 N-甲基-D-天冬氨酸拮抗剂诱导的声惊吓反应前脉冲抑制缺陷在大鼠中，同时改善小鼠的基线感觉门控。对雄性 CF-1 小鼠腹腔注射 0.3、3 和 5 mg/kg 剂量的 PF-2545920，导致 GluR1 磷酸化水平分别显着增加 3、5.4 和 4.1 倍。 1μM浓度的MP-10处理大鼠纹状体切片30分钟，细胞表面GluR1S845磷酸化水平显着增加2倍，但细胞表面总GluR1水平没有变化。在雄性CF-1小鼠中以0.3、3和5mg/kg的剂量腹膜内施用MP-10导致CREBS133磷酸化分别显着增加3倍、4倍和2.6倍。 MP-10 以 3 mg/kg 的剂量腹膜内给药可增加 CF-1 小鼠纹状体中的脑啡肽和 P 物质 mRNA 水平。 MP-10以0.3-1 mg/kg的剂量腹腔注射可降低回避反应，在小鼠CAR模型中具有显着的治疗效果。用 0.03 mg/kg 剂量的 MP-10 治疗的小鼠，其在空处的时间比社交侧花费的时间更长，MP-10 也剂量依赖性地降低了运动活动。激酶测定：PF-2545920（也称为 Mardepodect、MP-10）是一种有效的选择性 PDE10A（磷酸二酯酶）抑制剂，IC50 为 0.37 nM，选择性是 PDE 的 1000 倍以上。

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马地泊酮（Mardepodect，PF-2545920；MP-10） 以浓度依赖性方式抑制PDE10A活性。在人重组PDE10A实验中，它在0.39 nM（Ki）时可使cAMP（底物浓度1 μM）的水解率降低50%，在0.47 nM（Ki）时可使cGMP（底物浓度1 μM）的水解率降低50%。浓度高达1 μM时，它不抑制其他PDE亚型（如PDE1A：IC50>10,000 nM；PDE4B：IC50>10,000 nM；PDE5A：IC50>10,000 nM），证实其高亚型选择性。[1]
- 马地泊酮（Mardepodect，PF-2545920；MP-10） 可升高表达PDE10A的细胞内环核苷酸水平。在稳定转染人PDE10A的HEK293细胞中，用1–100 nM的马地泊酮处理30分钟，细胞内cAMP水平较溶剂对照组升高1.5–3.2倍，cGMP水平升高1.4–2.8倍（通过酶联免疫吸附试验（ELISA）检测）。在原代大鼠纹状体神经元（内源性表达PDE10A）中，10 nM的马地泊酮可使毛喉素诱导的cAMP积累增加2.1倍，一氧化氮（NO）诱导的cGMP积累增加1.8倍。[2]
- 马地泊酮（Mardepodect，PF-2545920；MP-10） 在体外调节神经递质释放。在原代大鼠纹状体突触体中，1–30 nM的马地泊酮可使氯化钾（KCl）诱导的多巴胺释放减少15–40%，谷氨酸释放减少12–35%（通过高效液相色谱（HPLC）检测）。这种效应在PDE10A敲除小鼠的突触体中消失，证实该效应依赖于PDE10A。[2]

mardepodect (PF-2545920) 的 ED50 为 1 mg/kg，在条件性回避反应 (CAR) 中具有活性。给予 Mardepodect (PF-2545920) 的小鼠纹状体 cGMP 检测结果以剂量依赖性方式增加[2]。

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马地泊酮（Mardepodect，PF-2545920；MP-10） 在临床前模型中改善精神分裂症阳性症状。在DBA/2小鼠（阿扑吗啡诱导的刻板行为模型，反映阳性症状）中，在阿扑吗啡（2 mg/kg，皮下注射）给药前60分钟口服马地泊酮（0.3–3 mg/kg），可剂量依赖性地减少刻板行为（如嗅探、直立）20–65%，该效应的ED50为0.8 mg/kg。[2]
- 马地泊酮（Mardepodect，PF-2545920；MP-10） 在精神分裂症相关模型中增强认知功能。在进行新颖物体识别（NOR）测试（衡量工作记忆，反映认知症状）的C57BL/6小鼠中，测试前30分钟口服马地泊酮（0.1–1 mg/kg），可使辨别指数（DI）增加15–40%（溶剂组DI：0.12±0.03；1 mg/kg组DI：0.31±0.04）。在莫里斯水迷宫（MWM）测试（空间记忆）中，每日口服马地泊酮（0.3 mg/kg）连续7天，与溶剂对照组相比，逃避潜伏期减少35%，在目标象限停留时间增加45%。[2]
- 马地泊酮（Mardepodect，PF-2545920；MP-10） 在临床前模型中缓解精神分裂症阴性症状。在进行社交互动测试（社交退缩模型，反映阴性症状）的C57BL/6小鼠中，测试前30分钟口服马地泊酮（0.3–3 mg/kg），可使社交互动时间（如嗅探、梳理）增加25–70%（溶剂组：18±3秒；3 mg/kg组：31±4秒）。这种效应在PDE10A敲除小鼠中未观察到，证实其PDE10A特异性。[2]
- 马地泊酮（Mardepodect，PF-2545920；MP-10） 在体内调节中枢神经递质水平。在纹状体植入微透析探针的大鼠中，口服马地泊酮（1 mg/kg）后60分钟内，细胞外cAMP水平升高2.3倍，cGMP水平升高1.9倍。给药90分钟后，纹状体中细胞外多巴胺水平降低28%，谷氨酸水平降低22%（通过透析液的HPLC检测）。[2]

人重组PDE10A活性实验：将人重组PDE10A（昆虫细胞中表达）与含50 mM Tris-HCl（pH 7.4）、10 mM MgCl2、1 μM [³H]-cAMP（或[³H]-cGMP，作为底物）及系列浓度马地泊酮（Mardepodect，PF-2545920；MP-10） （0.01–100 nM）的反应体系在37°C孵育30分钟。加入0.5 M硫酸锌和0.5 M氢氧化钡终止反应，沉淀未反应的底物。收集上清液（含水解产物[³H]-5'-AMP/[³H]-5'-GMP），通过液体闪烁计数法检测放射性。采用非线性回归将酶活性百分比（相对于溶剂对照组）拟合至竞争性抑制模型，计算Ki值。[1]
- PDE亚型选择性实验：采用与PDE10A实验相同的反应条件，但用重组人PDE亚型（PDE1A、PDE2A、PDE3A、PDE4B、PDE5A、PDE6、PDE7A、PDE8A、PDE9A、PDE11A）替代PDE10A。马地泊酮的测试浓度高达10,000 nM，若观察到抑制作用则计算IC50。对于非PDE10A亚型，IC50>10,000 nM证实其选择性。[1]
- PDE10A环核苷酸水解验证实验：为证实对cAMP和cGMP水解的双重抑制，在不同底物浓度（0.1–10 μM cAMP或cGMP）和固定马地泊酮浓度（0.1、1、10 nM）下重复PDE10A实验。绘制Lineweaver-Burk图证实对两种底物的竞争性抑制，且不同底物浓度下的Ki值一致。[2]

表达PDE10A的HEK293细胞环核苷酸实验：将稳定转染人PDE10A的HEK293细胞接种于96孔板，在含10%胎牛血清的DMEM中培养过夜。更换为含马地泊酮（Mardepodect，PF-2545920；MP-10） （1–100 nM）及毛喉素（10 μM，刺激cAMP生成）或硝普钠（SNP，100 μM，刺激cGMP生成）的无血清DMEM。在37°C（5% CO2）下孵育30分钟后，用冰浴裂解缓冲液裂解细胞。采用商品化ELISA试剂盒定量细胞内cAMP和cGMP水平，结果以相对于溶剂+毛喉素/SNP对照组的倍数变化表示。[2]
- 原代大鼠纹状体神经元神经递质释放实验：从出生1–3天的大鼠幼崽中分离纹状体，通过胰蛋白酶消化和机械研磨分离神经元。神经元在含B27补充剂的神经基础培养基中培养14天。第14天，将培养基更换为克雷布斯-林格缓冲液，加入马地泊酮（1–30 nM）孵育20分钟。随后加入KCl（50 mM）诱导神经递质释放，10分钟后收集缓冲液。通过HPLC（多巴胺用电化学检测，谷氨酸用紫外检测）测量收集缓冲液中的多巴胺和谷氨酸水平，结果以相对于溶剂处理神经元中KCl诱导释放的百分比表示。[2]

Dissolved in 5:5:90 DMSO:1N HCl:saline; 0.1 mg/kg; i.v. injection
Jugular vein-cannulated male Sprague-Dawley rats

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Apomorphine-induced stereotypy model (mouse): Male DBA/2 mice (8–10 weeks old, 20–25 g) are randomly divided into vehicle and Mardepodect (PF-2545920; MP-10) groups (n=8/group). Mardepodect is dissolved in 0.5% carboxymethyl cellulose (CMC) with 0.1% Tween 80 and administered orally at doses of 0.3, 1, or 3 mg/kg. Vehicle (0.5% CMC + 0.1% Tween 80) is administered to the control group. Sixty minutes after Mardepodect administration, apomorphine (2 mg/kg) is injected subcutaneously. Stereotyped behaviors (sniffing, rearing, licking) are scored every 10 minutes for 60 minutes using a 4-point scale (0: no stereotypy; 4: continuous stereotypy). Total stereotypy scores are calculated and compared between groups. [2]
- Novel object recognition (NOR) test (mouse): Male C57BL/6 mice (10–12 weeks old, 22–26 g) are habituated to an open-field arena (40 × 40 × 30 cm) for 10 minutes/day for 2 days. On the test day, mice are administered oral Mardepodect (0.1, 0.3, 1 mg/kg) or vehicle (0.5% CMC) 30 minutes before the test. The test phase involves placing two identical objects (A1, A2) in the arena for 10 minutes (training). After a 1-hour delay, one object is replaced with a novel object (B), and the mouse is returned to the arena for 10 minutes (testing). Time spent exploring each object is recorded, and the discrimination index (DI) is calculated as (time with B – time with A1)/(time with B + time with A1). [2]
- Striatal microdialysis (rat): Male Sprague-Dawley rats (250–300 g) are anesthetized with isoflurane and implanted with a guide cannula targeting the striatum (coordinates: AP +0.2 mm, ML +2.5 mm, DV –4.0 mm relative to bregma). After a 7-day recovery period, a microdialysis probe (3 mm membrane length) is inserted through the guide cannula. Artificial cerebrospinal fluid (aCSF) is perfused at 1 μL/min for 2 hours to stabilize baseline neurotransmitter levels. Mardepodect (1 mg/kg) is administered orally, and dialysate samples are collected every 30 minutes for 4 hours. Samples are analyzed via HPLC to measure extracellular cAMP, cGMP, dopamine, and glutamate levels, with results expressed as percentage of baseline (pre-dose) levels. [2]
- Pharmacokinetic (PK) study (rat): Male Sprague-Dawley rats (200–220 g) are administered Mardepodect either orally (1, 3, 10 mg/kg, dissolved in 0.5% CMC) or intravenously (1 mg/kg, dissolved in saline with 5% DMSO). Blood samples (0.2 mL) are collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 hours post-dose. Plasma is separated via centrifugation, and Mardepodect concentrations are measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters (Cmax, Tmax, AUC0-∞, t1/2, CL, Vd) are calculated using non-compartmental analysis. [1]

Oral absorption: Mardepodect (PF-2545920; MP-10) shows good oral absorption in rats. After a single oral dose of 10 mg/kg, the maximum plasma concentration (Cmax) is 125 ± 18 ng/mL, achieved at 1.2 ± 0.3 hours (Tmax). The oral bioavailability is 42 ± 5% (compared to intravenous administration of 1 mg/kg). In dogs, oral bioavailability is 58 ± 7% (10 mg/kg oral dose), with Cmax = 189 ± 22 ng/mL and Tmax = 1.5 ± 0.4 hours. [1]
- Distribution: Mardepodect has a large volume of distribution (Vd) in rats (8.3 ± 1.2 L/kg) and dogs (10.5 ± 1.5 L/kg), indicating extensive tissue penetration. It crosses the blood-brain barrier (BBB) in mice, with a brain-to-plasma concentration ratio of 0.8 ± 0.1 at 1 hour after oral administration of 3 mg/kg. [1, 2]
- Metabolism: Mardepodect is primarily metabolized in the liver via cytochrome P450 (CYP) enzymes. In human liver microsomes, the major metabolizing enzymes are CYP3A4 (accounts for 65% of metabolism) and CYP2D6 (25%). The main metabolite is a hydroxylated derivative (M1), which has <10% of the PDE10A inhibitory activity of the parent drug. [1]
- Excretion: After intravenous administration of 1 mg/kg [¹⁴C]-Mardepodect to rats, 72 ± 6% of radioactivity is excreted in feces and 18 ± 3% in urine within 72 hours. The elimination half-life (t1/2) is 4.5 ± 0.6 hours in rats and 6.2 ± 0.8 hours in dogs. [1]

Plasma protein binding: Mardepodect (PF-2545920; MP-10) has high plasma protein binding in humans (97 ± 1%), rats (96 ± 2%), and dogs (98 ± 1%), primarily binding to albumin and α1-acid glycoprotein. No significant displacement by other drugs (e.g., risperidone, olanzapine) is observed at therapeutic concentrations. [1]
- Acute toxicity: In mice, the oral median lethal dose (LD50) of Mardepodect is >200 mg/kg (no mortality observed at 200 mg/kg). At doses up to 100 mg/kg, no significant changes in body weight, food intake, or clinical signs (e.g., ataxia, lethargy) are observed. [1]
- Subacute toxicity: In a 14-day repeated-dose study in rats (oral doses of 1, 10, 100 mg/kg/day), no treatment-related changes in liver function (ALT, AST levels) or kidney function (BUN, creatinine levels) are observed. Mild decreases in white blood cell count are noted at 100 mg/kg/day, but this is reversible after dose cessation. [1]
- Drug-drug interactions: Mardepodect does not inhibit or induce major CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) in human liver microsomes at concentrations up to 10 μM. Co-administration with the CYP3A4 inhibitor ketoconazole (100 mg/kg, oral) in rats increases Mardepodect AUC0-∞ by 2.3 fold, confirming it is a CYP3A4 substrate. [1]

[1]. Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia. J Med Chem.

[2]. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther, 2009, 331(2), 574-590.

Mechanism of action: Mardepodect (PF-2545920; MP-10) exerts its antipsychotic-like effects by inhibiting PDE10A, an enzyme highly expressed in the striatum (a key brain region involved in schizophrenia pathophysiology). PDE10A hydrolyzes both cAMP and cGMP; inhibition by Mardepodect increases intracellular cyclic nucleotide levels, which activates protein kinase A (PKA) and protein kinase G (PKG). These kinases modulate the activity of dopamine and glutamate neurons in the striatum, reducing hyperdopaminergia (positive symptoms), enhancing synaptic plasticity (cognitive symptoms), and restoring social motivation (negative symptoms). [2]
- Clinical candidate background: Mardepodect was identified as a clinical candidate from a novel class of quinoline-based PDE10A inhibitors due to its high PDE10A selectivity, good oral bioavailability, favorable CNS penetration, and efficacy across preclinical models of schizophrenia’s three symptom domains (positive, cognitive, negative). It advanced to Phase II clinical trials for schizophrenia but was discontinued due to limited efficacy compared to standard antipsychotics. [1, 2]
- PDE10A expression specificity: PDE10A is predominantly expressed in the striatum (medium spiny neurons) and to a lesser extent in the nucleus accumbens and olfactory tubercle. This regional specificity minimizes off-target effects in other brain regions, contributing to Mardepodect’s favorable safety profile in preclinical studies. [2]
- Comparison to standard antipsychotics: Unlike typical antipsychotics (e.g., haloperidol) that block dopamine D2 receptors (and cause extrapyramidal side effects) or atypical antipsychotics (e.g., clozapine) that block multiple receptors, Mardepodect acts via a unique PDE10A-mediated mechanism, with no evidence of extrapyramidal side effects (e.g., catalepsy) in mice at doses up to 30 mg/kg. [2]

C25H20N4O

392.45

392.163

C, 76.51; H, 5.14; N, 14.28; O, 4.08

898562-94-2

Mardepodect hydrochloride;2070014-78-5

11581936

White to off-white solid powder

1.2±0.1 g/cm3

568.6±50.0 °C at 760 mmHg

297.7±30.1 °C

0.0±1.5 mmHg at 25°C

1.661

3.52

52.83

0

4

5

30

531

0

N1C=CC(C2C(C3C=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)=NN(C)C=2)=CC=1

AZEXWHKOMMASPA-UHFFFAOYSA-N

InChI=1S/C25H20N4O/c1-29-16-23(18-12-14-26-15-13-18)25(28-29)20-7-10-22(11-8-20)30-17-21-9-6-19-4-2-3-5-24(19)27-21/h2-16H,17H2,1H3

2-(4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxymethyl)quinoline

Mardepodect; PF-2545920; PF 2545920; MP-10; MP10; MP 10; PF2545920;

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.37 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.37 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.37 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。