[18F]-MC-225([18F]-MC-225) - 药物靶点：P-gp_在研适应症：阿尔茨海默症，轻度认知障碍，帕金森病_专利_临床

概要

基本信息

药物类型

诊断用放射药物

别名

Fluorine -18-MC-225、MC-225-[18F]

靶点

P-gp

作用机制

P-gp调节剂(P-糖蛋白-1调节剂)

治疗领域

神经系统疾病内分泌与代谢疾病免疫系统疾病+ [3]

在研适应症

阿尔茨海默症轻度认知障碍帕金森病+ [3]

非在研适应症-

原研机构

Hamamatsu Photonics KK

在研机构

University Medical Center Groningen

University Medical Center of Utrecht

Hamamatsu Photonics KK

+ [1]

非在研机构-

最高研发阶段临床1/2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

5

项与 [18F]-MC-225 相关的临床试验

EUCTR2022-003664-25-NL / Unknown status临床2期

The impact of gender differences in P-glycoprotein function measured with [18F]MC225 and PET - [18F]MC225 for measuring gender differences

开始日期2023-12-21

申办/合作机构

University Medical Center Groningen

NCT05618119 / Not yet recruitingN/A

The Impact of Gender Differences in P-glycoprotein Function Measured With [18F]MC225 and PET

P-gp is one of the main efflux transporters at the blood-brain barrier and is responsible for the transport of a variety of neurotoxic substances, including pharmaceuticals. Multiple studies report gender differences in therapeutic outcomes, toxicity and side effects for many drug agents. P-gp plays an important role in the bio-availability, drug distribution, metabolism and elimination of pharmaceuticals labelled as P-gp substrates (e.g. the majority of antidepressants and antipsychotics). A difference in P-gp function was already reported in hepatic P-gp expression. The aim of the current study is to evaluate the influence of gender on cerebral P-gp function. Outcomes of this study can be of great importance in gender-based prescription of P-gp substrate pharmaceuticals.

开始日期2023-01-01

申办/合作机构

University Medical Center Groningen

NCT05853471 / Recruiting临床1/2期

Evaluation of [18F]MC225-PET to Measure P-glycoprotein Function in Neurodegenerative Disease

P-glycoprotein, an efflux transporter at the blood-brain barrier plays an important role in de development of neurodegenerative disease. A novel PET tracer ([18F]MC225) was developed to measure the function of P-glycoprotein and was tested with succes in healthy volunteers. This study aims to evaluate [18F]MC225 in neurodegenerative disease.

开始日期2022-02-01

申办/合作机构

University Medical Center Groningen

100 项与 [18F]-MC-225 相关的临床结果

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100 项与 [18F]-MC-225 相关的转化医学

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100 项与 [18F]-MC-225 相关的专利（医药）

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5

项与 [18F]-MC-225 相关的文献（医药）

2022-07-01·Journal of Controlled Release1区 · 医学

Dose-response assessment of cerebral P-glycoprotein inhibition in vivo with [18F]MC225 and PET

1区 · 医学

Article

作者: Aguiar, Pablo ; van Waarde, Aren ; Dierckx, Rudi A J O ; Vazquez-Matias, Daniel A ; Bartels, Anna L ; Willemsen, Antoon T M ; Luurtsema, Gert ; Elsinga, Philip H ; Garcia-Varela, Lara ; Colabufo, Nicola A ; Mossel, Pascalle

The Blood-Brain Barrier P-glycoprotein (P-gp) function can be altered in several neurodegenerative diseases and due to the administration of different drugs which may cause alterations in drug concentrations and consequently lead to a reduced effectiveness or increased side-effects. The novel PET radiotracer [¹⁸F]MC225 is a weak P-gp substrate that may show higher sensitivity to detect small changes in P-gp function than previously developed radiotracers. This study explores the sensitivity of [¹⁸F]MC225 to measure the dose-dependent effect of P-gp inhibitor tariquidar. Twenty-three rats were intravenously injected with different doses of tariquidar ranging from 0.75 to 12 mg/kg, 30-min before the dynamic [¹⁸F]MC225-PET acquisition with arterial sampling. Tissue and blood data were fitted to a 1-Tissue-Compartment-Model to obtain influx constant K₁ and distribution volume V_T, which allow the estimation of P-gp function. ANOVA and post-hoc analyses of K₁ values showed significant differences between controls and groups with tariquidar doses >3 mg/kg; while applying V_T the analyses showed significant differences between controls and groups with tariquidar doses >6 mg/kg. Dose-response curves were fitted using different models. The four-parameter logistic sigmoidal curve provided the best fit for K₁ and V_T data. Half-maximal inhibitory doses (ID₅₀) were 2.23 mg/kg (95%CI: 1.669-2.783) and 2.93 mg/kg (95%CI: 1.135-3.651), calculated with K₁ or V_T values respectively. According to the dose-response fit, differences in [¹⁸F]MC225-K₁ values could be detected at tariquidar doses ranging from 1.37 to 3.25 mg/kg. Our findings showed that small changes in the P-gp function, caused by low doses of tariquidar, could be detected by [¹⁸F]MC225-K₁ values, which confirms the high sensitivity of the radiotracer. The results suggest that [¹⁸F]MC225 may allow the quantification of moderate P-gp impairments, which may allow the detection of P-gp dysfunctions at the early stages of a disease and potential transporter-mediated drug-drug interactions.

2021-12-01·European Journal of Nuclear Medicine and Molecular Imaging1区 · 医学

Head-to-head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

1区 · 医学

Article

作者: Elsinga, Philip H ; Vállez García, David ; Aguiar, Pablo ; Colabufo, Nicola A ; Luurtsema, Gert ; Tago, Tetsuro ; Tsukada, Hideo ; Ohba, Hiroyuki ; García-Varela, Lara ; van Waarde, Aren ; Nishiyama, Shingo ; Dierckx, Rudi A J O ; Boellaard, Ronald ; Harada, Norihiro ; Toyohara, Jun ; Kakiuchi, Takeharu

AbstractPurposeP-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects.MethodsThree non-human primates underwent 4 PET scans: 2 with (R)-[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite-corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed.ResultsAt baseline, [18F]MC225 VT values were higher, and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After inhibition, VT values of the 2 tracers were similar; however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers.Conclusion[18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT.

2021-12-01·EJNMMI Radiopharmacy and Chemistry

A new approach to produce [18F]MC225 via one-step synthesis, a PET radiotracer for measuring P-gp function

Article

作者: Jacquet, Olivier ; Elsinga, Philip H ; Kwizera, Chantal ; Dierckx, Rudi A J O ; Visser, Ton J ; Antunes, Inês F ; Luurtsema, Gert ; Garcia-Varela, Lara ; Attia, Khaled ; Sembrano, John Carlo

AbstractBackground[18F]MC225 is a radiotracer for imaging P-glycoprotein (P-gp) function at the blood-brain barrier. The P-gp function can be altered due to different factors, for instance, decreased P-gp function has been described in patients with Alzheimer’s or Parkinson’s Disease. The current applied radiosynthesis of [18F]MC225 involves 2 steps, including the distillation of the [18F] fluoroethylbromide intermediate. To develop a more robust synthetic procedure, it is of interest to produce the radiotracer via a 1-step synthesis. The present study describes a new synthetic approach to produce [18F]MC225 via direct 18F-fluorination. Moreover, we also provide the appropriate conditions for the automation of the synthesis. A mesylate precursor was synthesized via a multi-step synthetic route and used for the radiolabeling. The nucleophilic substitution of the mesylate group by [18F] Fluoride was automated in two different synthesis modules: IBA Synthera and Eckert and Ziegler PharmTracer (E&Z).ResultsThe mesylate precursor was synthesized in 7 steps starting with 5-hydroxy-1-tetralone (commercially available) in practical yields. The stability of the precursor was improved via mesylate salt formation method. The radiolabeling was done by adding the mesylate precursor dissolved in DMF to the dried [18F]KF/K2.2.2 complex and heating at 140 °C for 30 min. Quality control by UPLC confirmed the production of [18F]MC225 with a molar activity (Am) higher than 100 GBq/micromole. The synthesis time in Synthera was 106 min and the product was obtained with a radiochemical purity higher than 95% and RCY of 6.5%, while the production in E&Z lasted 120 min and the product had a lower radiochemical purity (91%) and RCY (3.8%).Conclusions[18F]MC225 was successfully produced via a 1-step reaction. The procedure is suitable for automation using commercially available synthesis modules. The automation of the radiosynthesis in the Synthera module allows the production of the [18F]MC225 by a reliable and simple method.

100 项与 [18F]-MC-225 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床2期	荷兰	University Medical Center Groningen	2022-02-01
轻度认知障碍	临床2期	荷兰	University Medical Center Groningen	2022-02-01
帕金森病	临床2期	荷兰	University Medical Center Groningen	2022-02-01
HIV感染	临床前	日本	Hamamatsu Photonics KK	-
HIV感染	临床前	荷兰	University Medical Center of Utrecht	-
HIV感染	临床前	日本	The Tokyo Metropolitan Institute of Gerontology	-
神经系统疾病	临床前	日本	The Tokyo Metropolitan Institute of Gerontology	-
神经系统疾病	临床前	荷兰	University Medical Center of Utrecht	-
神经系统疾病	临床前	日本	Hamamatsu Photonics KK	-
老化	临床前	荷兰	University Medical Center of Utrecht	-