In vivo evaluation of radiotracers targeting the melanin-concentrating hormone receptor 1: [11C]SNAP-7941 and [18F]FE@SNAP reveal specific uptake in the ventricular system

Markus Zeilinger,Helmut Spreitzer,Wolfgang Wadsak,Florian Pichler,Cécile Philippe,Lubos Budinsky,Katharina Pallitsch,Rupert Lanzenberger,Monika Dumanic,Markus Mitterhauser,Marcus Hacker

doi:10.1038/s41598-017-08684-6

Abstract

The MCHR1 is involved in the regulation of energy homeostasis and changes of the expression are linked to a variety of associated diseases, such as diabetes and adiposity. The study aimed at the in vitro and in vivo evaluation of [11C]SNAP-7941 and [18F]FE@SNAP as potential PET-tracers for the MCHR1. Competitive binding studies with non-radioactive derivatives and small-animal PET/CT and MRI brain studies were performed under baseline conditions and tracer displacement with the unlabelled MCHR1 antagonist (±)-SNAP-7941. Binding studies evinced high binding affinity of the non-radioactive derivatives. Small-animal imaging of [11C]SNAP-7941 and [18F]FE@SNAP evinced high tracer uptake in MCHR1-rich regions of the ventricular system. Quantitative analysis depicted a significant tracer reduction after displacement with (±)-SNAP-7941. Due to the high binding affinity of the non-labelled derivatives and the high specific tracer uptake of [11C]SNAP-7941 and [18F]FE@SNAP, there is strong evidence that both radiotracers may serve as highly suitable agents for specific MCHR1 imaging.

Highlights

The melanin-concentrating hormone (MCH) is a cyclic polypeptide consisting of 19 amino acids, produced predominantly by neurons in the lateral hypothalamus, incerto-hypothalamic area and zona incerta with extensive projections throughout the brain[1]
The in vivo quantification of MCH receptor 1 (MCHR1) pharmacology is a crucial step for the better understanding of the pathogenesis of a variety of endocrine disorders like obesity, diabetes and insulin resistance
A specific positron emission tomography (PET) radiotracer for MCHR1 imaging is of high scientific interest, since it comprises several advantages for clinical medicine and biomedical research, such as monitoring of the hormone receptor status and related pathologies in-vivo, compound dose selection and the in vivo quantification of the MCHR1 as a risk factor and early diagnostic tool for adiposity, diabetes and insulin resistance

Summary

Introduction

The melanin-concentrating hormone (MCH) is a cyclic polypeptide consisting of 19 amino acids, produced predominantly by neurons in the lateral hypothalamus, incerto-hypothalamic area and zona incerta with extensive projections throughout the brain[1]. Given the fact that ependymal cells and MCH neurons are both involved in glucose sensing[24,25,26], MCH fibres could control the activity of ciliated cells to initiate an increase in CSF flow to meet metabolic needs This strongly supports the idea that the MCH-system may be involved in non-neuronal intercellular communication, but evidence is still lacking. Based on the specific MCHR1 antagonist (+)-methyl(4 S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1piperidinyl}propyl)amino] carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetra-hydro-5-pyrimidenecarboxylate hydrochloride ((+)-SNAP-7941; Fig. 1a)[27], the successful preparation of the first potential PET radiotracers [11C] SNAP-7941 (Fig. 1b) and the [18F]fluoroethylated analogue [18F]FE@SNAP (Fig. 1c) was performed[28, 29] Since both tracers yield adequate amounts of radioactivity with suitable molar activity, initial preclinical evaluation has been accomplished[30, 31]. The aims of the study were (i) competitive binding studies with the non-radioactive derivatives, (ii) small-animal PET/CT and MRI studies of healthy rats with MCHR1 displacement and (iii) small-animal PET/CT and MRI studies of healthy rats under baseline conditions

Objectives

Methods

Results

Conclusion