Preclinical in vitro &amp; in vivo evaluation of [11C]SNAP-7941 – the first PET tracer for the melanin concentrating hormone receptor 1

Philippe, Cécile; Nics, Lukas; Zeilinger, Markus; Kuntner, Claudia; Wanek, Thomas; Mairinger, Severin; Shanab, Karem; Spreitzer, Helmut; Viernstein, Helmut; Wadsak, Wolfgang; Mitterhauser, Markus

doi:10.1016/j.nucmedbio.2013.05.010

Cited by 18 publications

(22 citation statements)

References 29 publications

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“…Nevertheless, no metabolite was found in the rat brains of the baseline and TQD-pretreatment group [74].…”

Section: Melaninmentioning

confidence: 85%

“…As mentioned before, Borowsky et al [51] presented the evaluation of the very potent MCHR1 antagonist SNAP-7941, which contains a methyl ester (Figure 3(1)), making it suitable for radiolabeling introducing either a [ 11 C]methyl moiety or a 2-[ 18 F]fluoroethyl moiety. On this basis, two potential PET tracers for the visualization of the MCHR1 were developed so far: Figure 3(2)) and [ 18 F]FE@SNAP (Figure 3(3)) [73][74][75][76][77].…”

Section: Diagnostic Imagingmentioning

confidence: 99%

“…Radiochemical purity always exceeded 99% [73]. The specific radioactivity for the preclinical in vivo evaluation was 108.2 ± 56 GBq/μmol at the end of synthesis (EOS) [74]. The full radiosynthesis, purification procedure, and physiological formulation could be automated to guarantee a safe and reliable production.…”

Section: Melaninmentioning

confidence: 99%

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The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends

Philippe¹,

Mitterhauser²

2017

Melanin

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The neuropeptide melanin-concentrating hormone (MCH) plays a key role in energy maintenance by decreasing energy expenditure and stimulating feeding behavior. Furthermore, it is involved in diabetes, gut inflammation, sleep, depression, and cilia beat function. The biological function of MCH is mediated by two G-protein coupled receptors, MCH receptor 1 and 2 (MCHR1 and MCHR2). Since only the MCHR1 is functional in rodents, the physiological importance of MCHR2 remains unknown due to the lack of appropriate animal models. The involvement of the MCHergic system in a variety of pathologies, especially endocrinological diseases, such as obesity and diabetes, makes it interesting as a new target to treat human disorders. Many pharmaceutical companies have pursued the development of MCHR1 antagonists for the treatment of obesity. Moreover, positron emission tomography (PET) tracers targeting the MCHR1 have been developed in order to gain a deeper understanding of the role and distribution of the MCHR1. As a high-end technique, PET allows noninvasive in vivo visualization and quantification of receptor systems, as well as monitoring and following hormone receptor status and related pathologies. Therefore, a MCHR1 PET tracer could help to guide pharmacological intervention via the MCHR1.

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“…Nevertheless, no metabolite was found in the rat brains of the baseline and TQD-pretreatment group [74].…”

Section: Melaninmentioning

confidence: 85%

Section: Diagnostic Imagingmentioning

confidence: 99%

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The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends

Philippe¹,

Mitterhauser²

2017

Melanin

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“…Thus, SNAP-acid 2 finally served as precursor for the radiosynthetically produced tracer [ [15,16]. After radioactive labeling at the Medical University of Vienna [15,16], biodistribution and micro PET experiments will be the next step of this ongoing project, as recently shown by Philippe et al [40].…”

Section: Discussionmentioning

confidence: 97%

Syntheses of Precursors and Reference Compounds of the Melanin-Concentrating Hormone Receptor 1 (MCHR1) Tracers [11C]SNAP-7941 and [18F]FE@SNAP for Positron Emission Tomography

et al. 2013

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Abstract:The MCH receptor has been revealed as a target of great interest in positron emission tomography imaging. The receptor′s eponymous substrate melanin-concentrating hormone (MCH) is a cyclic peptide hormone, which is located predominantly in the hypothalamus with a major influence on energy and weight regulation as well as water balance and memory. Therefore, it is thought to play an important role in the pathophysiology of adiposity, which is nowadays a big issue worldwide. Based on the selective and high-affinity MCH receptor 1 antagonist SNAP-7941, a series of novel SNAP derivatives has been developed to provide different precursors and reference compounds for the radiosyntheses of the novel PET radiotracers [ Positron emission tomography promotes a better understanding of physiologic parameters on a molecular level, thus giving a deeper insight into MCHR1 related processes as adiposity.

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“…Compared to [ 11 C]SNAP-7941, which we evaluated previously [34], [ 18 F]FE@SNAP was only accessible via microfluidic chemistry. Both tracers evinced a high binding affinity and selectivity to hMCHR1 and a high metabolic stability in human plasma and against liver microsomes and carboxylesterase.…”

Section: Discussionmentioning

confidence: 99%

Preparation and First Preclinical Evaluation of [18F]FE@SNAP: A Potential PET Tracer for the Melanin Concentrating Hormone Receptor 1 (MCHR1)

Philippe

Nics

Zeilinger³

et al. 2013

Sci. Pharm.

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The melanin-concentrating hormone (MCH) system is a new target for the treatment of human disorders. Since the knowledge of the MCH system’s involvement in a variety of pathologies (obesity, diabetes, and deregulation of metabolic feedback mechanism) is based on in vitro or preclinical studies, a suitable positron emission tomography (PET) tracer needs to be developed. We herein present the preparation and first preclinical evaluation of [18F]FE@SNAP – a new PET tracer for MCH receptor-1 (MCHR1). The synthesis was performed using a microfluidic device. Preclinical evaluation included binding affinity, plasma stability, plasma free fraction, stability against the cytochrome P-450 (CYP450) system using liver microsomes, stability against carboxyl-esterase, and methods to assess the penetration of the blood-brain barrier (BBB) such as logD analysis and immobilized artificial membrane (IAM) chromatography. Levels at 374 ± 202 MBq [18F]FE@SNAP were obtained after purification. The obtained Kd value of [18F]FE@SNAP was 2.9 nM. [18F]FE@SNAP evinced high stability against carboxylesterase, CYP450 enzymes, and in human plasma. LogD (3.83) and IAM chromatography results (Pm=0.51) were in the same range as for known BBB-penetrating compounds. The synthesis of [18F]FE@SNAP was reliable and successful. Due to high binding affinity and stability, [18F]FE@SNAP is a promising tracer for MCHR1.

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Preclinical in vitro & in vivo evaluation of [11C]SNAP-7941 – the first PET tracer for the melanin concentrating hormone receptor 1

Cited by 18 publications

References 29 publications

The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends

The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends

Syntheses of Precursors and Reference Compounds of the Melanin-Concentrating Hormone Receptor 1 (MCHR1) Tracers [11C]SNAP-7941 and [18F]FE@SNAP for Positron Emission Tomography

Preparation and First Preclinical Evaluation of [18F]FE@SNAP: A Potential PET Tracer for the Melanin Concentrating Hormone Receptor 1 (MCHR1)

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