Abstract
PurposeThe melanin-concentrating hormone receptor 1 (MCHR1) has become an important pharmacological target, since it may be involved in various diseases, such as diabetes, insulin resistance, and obesity. Hence, a suitable positron emission tomography radiotracer for the in vivo assessment of the MCHR1 pharmacology is imperative. The current paper contrasts the extensive in vitro, in vivo, and ex vivo assessments of the radiotracers [18F]FE@SNAP and [11C]SNAP-7941 and provides comprehensive information about their biological and physicochemical properties. Furthermore, it examines their suitability for first-in-man imaging studies.ProceduresKinetic real-time cell-binding studies with [18F]FE@SNAP and [11C]SNAP-7941 were conducted on adherent Chines hamster ovary (CHO-K1) cells stably expressing the human MCHR1 and MCHR2. Small animal imaging studies on mice and rats were performed under displacement and baseline conditions, as well as after pretreatment with the P-glycoprotein/breast cancer resistant protein inhibitor tariquidar. After the imaging studies, detailed analyses of the ex vivo biodistribution were performed. Ex vivo metabolism was determined in rat blood and brain and analyzed at various time points using a quantitative radio-HPLC assay.Results[11C]SNAP-7941 demonstrates high uptake on CHO-K1-hMCHR1 cells, whereas no uptake was detected for the CHO-K1-hMCHR2 cells. In contrast, [18F]FE@SNAP evinced binding to CHO-K1-hMCHR1 and CHO-K1-hMCHR2 cells. Imaging studies with [18F]FE@SNAP and [11C]SNAP-7941 showed an increased brain uptake after tariquidar pretreatment in mice, as well as in rats, and exhibited a significant difference between the time-activity curves of the baseline and blocking groups. Biodistribution of both tracers demonstrated a decreased uptake after displacement. [11C]SNAP-7941 revealed a high metabolic stability in rats, whereas [18F]FE@SNAP was rapidly metabolized.ConclusionsBoth radiotracers demonstrate appropriate imaging properties for the MCHR1. However, the pronounced metabolic stability as well as superior selectivity and affinity of [11C]SNAP-7941 underlines the decisive superiority over [18F]FE@SNAP.
Highlights
The mammalian melanin-concentrating hormone (MCH), a cyclic 19 amino acid long polypeptide, is primarily produced by neurons in the lateral hypothalamic area (LHA), the incerto-hypothalamic area (IHy), and zona incerta (ZI) [1]
Kinetic real-time cell-binding studies were performed in a reliable manner with high temporal resolution as shown in Fig. 2. [18F]FE@SNAP and [11C]SNAP-7941 demonstrate high accumulation on CHO-K1-hMCHR1 cells, whereas negligible accumulation was detected for the native CHOK1 cells
High statistical significance was observed for the accumulation of both radiotracers on the native CHO-K1 cells compared to the CHO-K1-hMCHR1 cells (P G 0.0001, Fig. 2a)
Summary
The mammalian melanin-concentrating hormone (MCH), a cyclic 19 amino acid long polypeptide, is primarily produced by neurons in the lateral hypothalamic area (LHA), the incerto-hypothalamic area (IHy), and zona incerta (ZI) [1]. The biological function of MCH is mediated by two G-protein coupled receptors (GPCRs): MCH receptor 1 (MCHR1) [6,7,8,9] and MCH receptor 2 (MCHR2) [10,11,12,13]. Considering the expression of MCH and MCHR1, the ventricular system, LHA, IHy, ZI, adipose tissue, lung, pancreas, spleen, colon, eyes, as well as muscle tissue are considered primary target regions [2, 3, 6, 11, 23, 24, 26,27,28]. The specific MCHR1 antagonist SNAP-7941 ((+)-methyl(4S)-3-{[(3-{4-[3(acetylamino)phenyl]-1piperidinyl}propyl)amino]carbonyl}-4(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidenecarboxylate hydrochloride) [31] served as model for the first MCHR1 PET tracers: [11C]SNAP-7941 (Fig. 1a), which is the radiolabeled analog of SNAP-7941 and [18F]FE@SNAP, a [18F]fluoroethylated derivative (Fig. 1b) [32,33,34,35,36,37,38]
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