18f and 11c radiolabeled MCHR1 pet ligands

Abstract

The present invention provides radiolabeled 2, 3, 4, 5 -tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl]pyridin-2(1H)-one derivatives of general formula (I) or salts thereof and precursors of formulae (II) and (III) to said radioligands, to processes for the preparation thereof, and to intermediates of said processes. The radiolabeled compounds enable visualization and quantification of melanin concentrating hormone receptor 1 (MCHR1) receptors in various target tissues, including monitoring the MCHR1 in such target tissue. The compounds exhibit high binding affinity towards MCHR1 and can pass the blood-brain barrier, thereby facilitate the diagnosis of a range of disease states in human clinical research.

Description

[0001]18F AND11C RADIOLABELED MCHR1 PET LIGANDS THE FIELD OF THE INVENTION The present invention relates to radiolabeled 2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl]pyridin-2(1H)-one derivatives of general formula (I) and / or salts thereof, which are useful for binding and imaging melanin-concentrating hormone receptor 1 (MCHR1) in a mammal’s brain. Also, the present invention relates to certain precursors of formula (II) to said radioligands, to processes for the preparation thereof, and to intermediates of said processes. THE BACKGROUND OF THE INVENTION Numerous medical diagnostic procedures utilize radiolabeled compounds. PET (positron emission tomography) is one of the very sensitive techniques which requires small quantities of radiolabeled compounds, called tracers. The labeled compounds are absorbed, distributed, metabolized, and eliminated in vivo the same way as the corresponding non- radioactive compounds. Tracers can be radiolabeled with a radionuclide useful for PET imaging, such as11C,13N,18F,64Cu,68Ga,82Rb and124I. The PET method detects malfunction on cellular level in the investigation of tissues and organs. PET has been used in clinical oncology (imaging the tumors and metastases), in identification of specific brain diseases and mapping brain and heart functions. Carbon-11 (t1 / 2 = 20.3 min) is one of the most frequently used radioisotopes in PET because of its abundance in organic molecules and short half-life which allows for multiple tracer administration on the same day to the same mammal, i.e., human or animal subject and reduces the radiation burden on the patients. Radiolabeling target molecules with carbon-11 is more challenging due to the shorter half-life of carbon-11 that prohibits long-run synthesis, and multistep reactions. Some effective strategies must consider carbon-11 radiochemistry, which include the design of reaction method in a way that carbon-11 radionuclide should be introduced in the last step. The11C-tracer is then purified by HPLC, which significantly increases the loss of the tracer and production time, and complicates automation. The radiochemistry of fluorine-18 (t1 / 2= 109.7 min), another widely used PET isotope, has been recently advanced via the development of cassette-based kits that obviate the need for HPLC purification. By employing solid phase extraction (SPE) cartridges, these fully disposable kits allow the reliable routine production of18F-tracers, including [18F]FDG and others, with shorter synthesis times, reduced personnel involvement and minimal maintenance of the equipment. Their development would significantly improve synthetic reliability, increase radiochemical yields, and simplify automation and preventive maintenance of the production modules. 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 with extensive projections throughout the brain (Bittencourt, Gen Comp Endocrinol 2011, 172:185–97. The biological effects of MCH are mediated by two G-protein coupled receptors (GPCRs), termed MCH receptor 1 (MCHR1) (Saito et al., Nature 1999, 400:265–69, Shimomura et al., Biochem Biophys Res Commun 1999, 261:622–26) and MCH receptor 2 (MCHR2) (Sailer et al., Proc Natl Acad Sci USA 2001, 98:7564–69). Since only the MCHR1 is functional in rodents, the physiological importance of MCHR2 remains unknown due to the lack of appropriate animal models. The distribution of MCH and the expression of the MCHR1 in the brain outside of regions connected with nutritional behavior, has led to the finding that MCH signaling is also involved in a variety of psychiatric disorders, such as depression and anxiety (Smith et al., Neuropsychopharmacology 2006, 31:1135–45). Given the fact that ependymal cells and MCH neurons are both involved in glucose sensing (Guyon et al., J Neurosci 2009, 29:2528– 33) MCH fibers 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 also be involved in non-neuronal intercellular communication, but evidence is still lacking. Antagonism of MCHR1 is one of the viable targets for obesity therapy (Pissios, Peptides 2009, 30:2040-44). Among orexigenic peptides in the hypothalamus, MCH is the only known peptide whose ablation results in leanness (Rivera et al., Curr Med Chem 2008, 15:1025-43). However, to enable a quantitative in vivo assessment of the MCHR1 pharmacology and to facilitate preclinical to clinical translation, a suitable PET tracer needs to be developed. SNAP-7941 is a potent MCHR1 antagonist, which contains a methyl ester (Figure 1, Compound A), making the molecule suitable for introducing either a [11C]methyl moiety or a [18F]fluoroethyl moiety (Borowsky et al. Nat Med 2002, 8:825–30). On this basis, potential PET tracers for the visualization of the MCHR1 were developed such as [11C]SNAP-7941 (Figure 1, Compound B) and [18F]FE@SNAP (Figure 1, Compound C). These tracers have some disadvantages: [11C]SNAP-7941 was a PGP substrate so its uptake in brain was low, [18F]FE@SNAP was not selective against MCHR2, furthermore, both compounds suffered from low rat plasma stabilities (Philippe et al., Nucl Med Biol 2013, 40:919-25; Philippe et al., Mol Imag Biol 2019, 21:257-68; Philippe et al., Sci Pharm 2013, 81:625-39). Takeda reported a carbon-11 MCHR1 radioligand (Figure 1, Compound D), which was also a substrate for efflux transporters in rats (Igawa et al., Curr Radiopharm 2017, 10:35- 40). Its limited brain uptake increased after the pretreatment with cyclosporine A (CSA), which is a drug transporter inhibitor (Panfen et al., Drug Met. Disp. 2019, 47(11):1352-60; Yang et al. Int. J. Mol. Sci.2020, 21(19): 7023-50). Banyu Pharmaceutical has reported a selective potent MCHR1 antagonist TC-MCH 7c (Figure 1, Compound E) that contains a fluorine atom connected to an aromatic ring, which was an ideal compound for the synthesis and investigations of an 18-fluorine tracer (Haga et al., Bioorg Med Chem 2011, 19:883-93; Mikecz et al., Nucl Med Rev 2017, 20(2):111, Abstr.T1-1). The authors claimed that the labeled compound shows specific uptake in the hypothalamus area of the brain in healthy rats, but further investigations have not been published until now. Diazepino-indole derivatives have selective antagonistic effect on the MCHR1 receptors that is known in the art (WO 2016 / 166684 A1) but structurally close radiolabeled MCHR1 PET ligands have not been synthesized so far. Summarizing the literature data, although MCHR1 PET radioligands have been developed but none of them was shown to be suitable for clinical research so far. Accordingly, there is an unmet need to provide MCHR1 PET radioligands that can be useful in human clinical research. SUMMARY OF THE INVENTION The present invention relates to a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salt thereof. The present invention also relates to a precursor compound of general formula (II) or a salt thereof. The present invention also relates to a precursor compound of general formula (III) or a salt thereof. In addition, the present invention relates to a process for the preparation of a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of a precursor compound of general formula (II) or a pharmaceutically acceptable salt thereof. The present invention relates to a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salt thereof for use as PET tracers. BRIEF DESCRIPTION OF THE FIGURES Figure 1: Structures of MCHR1 PET ligands known in the art. Figure 2: In vivo dynamic PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Example 8. Representative decay-corrected dynamic PET images (Figure 2A) and SUVmean time-activity curve (TAC) (Figure 2B) of Example 8 in the brain of healthy Wistar rats. Black circles: brain area. Figure 3: In vivo dynamic PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Example 9. Representative decay-corrected dynamic PET images (Figure 3A) and SUVmean time-activity curve (TAC) (Figure 3B) of Example 9 in the brain of healthy Wistar rats. Black circles: brain area. Figure 4: In vivo dynamic PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Example 10. Representative decay-corrected dynamic PET images (Figure 4A) and SUVmean time-activity curve (TAC) (Figure 4B) of Example 10 in the brain of healthy Wistar rats. Black circles: brain area. Figure 5: In vivo PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Reference Example 3 alone and after CSA pretreatment. Representative decay-corrected summa PET images (0 – 180 min, Figure 5A) and SUVmean time-activity curve (TAC) (Figure 5B). Black circles are the brain area. Figure 6: In vivo PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Example 11 alone and after CSA pretreatment. Representative decay- corrected static PET images (0 – 40 min, Figure 6A) and SUVmean time-activity curve (TAC) (Figure 6B). Black circles and arrows are brain area. Figure 7: Ex vivo biodistribution 30 and 180 min after the intravenous injection of Example 8 in healthy control Wistar rats. Figure 8: PET / MRI summation images between 40-60 min (Figure 8A) and PET / CT summation images between 80-100 min (Figure 8B) in the cynomolgus monkey brain after receiving a single i.v. injection of Example 8. Black circles indicate the higher PET concentrations. Figure 9: Regional TAC recorded from the brain of cynomolgus monkey. The images from 4 regions of encephalon (Figure 9A) and from 4 regions of lobe (Figure 9B) after receiving a single i.v. injection of Example 8. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a radiolabeled compound of general formula (I): wherein A is CH or N; R1is18F and R2is CH3, or CH(CH3)2group, or R1is F and R2is11CH3group, or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of general formula (I) is a compound wherein A is CH or N, R1is18F, R2is CH3, or CH(CH3)2group, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of general formula (I) is a compound wherein A is CH , R1is18F, R2is CH3, or CH(CH3)2group, or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of general formula (I) is a compound wherein A is CH or N, R1is F, R2is11CH3, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of general formula (I) is a compound wherein A is CH, R1is F, R2is11CH3, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the radiolabeled compound of general formula (I) is selected from the group consisting of: 4-{[4-(18F)fluorophenyl]methoxy}-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl]pyridin-2(1H)-one, 4-{[4-(18F)fluorophenyl]methoxy}-1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a] indol-9-yl)pyridin-2(1H)-one, 4-[(4-Fluorophenyl)methoxy]-1-[3-(11C)methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a] indol-9-yl]pyridin-2(1H)-one, 4-[(5-Fluoropyridin-2-yl) methoxy]-1-[3-(11C)methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl]pyridin-2(1H)-one, and a pharmaceutically acceptable salt thereof. The present invention also relates to a fluorine-18 precursor compound of general formula (II): wherein R1is B(O-C(R3)2-C(R3)2-O) group; R2is CH3, CH(CH3)2, or COOC(CH3)3group; R3is CH3 or C2H5 group, or a salt thereof. In another embodiment, the compound of the general formula (II) is selected from the group consisting of: 1-[3-(Propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl]-4-{[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyridin-2(1H)-one, 1-(3-Methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)-4-{[4-(4,4,5,5- tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyridin-2(1H)-one, 4-{[4-(4,4,5,5-Tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}-1-(2,3,4,5-tetrahydro- 1H-[1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one hydrochloride salt, and tert-Butyl 9-[2-oxo-4-{[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy} pyridin-1(2H)-yl]-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate. The present invention also relates to a carbon-11 precursor compound of general formula (III): wherein A is CH or N, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of the general formula (III) is selected from the group consisting of: 4-[(4-fluorophenyl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9- yl)pyridin-2(1H)-one maleate salt, and 4-[(5-fluoropyridin-2-yl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7- a]indol-9-yl)pyridin-2(1H)-one maleate salt. The present invention relates to a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salt thereof for use as PET tracers. The present invention also relates to a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salts thereof for use in visualizing localization or distribution of MCHR1 receptors in mammals by means of PET imaging, including rodents, NHPs and humans. The term ‘mammal’ refers to any vertebrate animal of the class Mammalia, including, but not limited to, guinea pig, any rodent (such as hamster, mouse, rat), any non-human primate (such as cynomolgus macaque, rhesus macaque, baboon, marmoset, and green monkey) or human subject. The present invention also relates to a process for the preparation of a compound of general formula (I). The present invention also relates to a process for the preparation of a compound of general formula (II). Accordingly, a compound of general formula (I) or a compound of general formula (II) can be prepared by one of the following methods. List of abbreviations used in the general synthesis and the Examples: AcOH = acetic acid MeCN = acetonitrile Ar = argon MeOH = methanol [11C]MeOTf = [11C]methyl triflate MgSO4 = magnesium sulfate CSA = cyclosporine A min = minute(s) Cs2CO3= cesium carbonate Na2SO4= sodium sulfate Cu(OTf)2(py)4= NaBH(OAc)3= sodium triacetoxy tetrakis(pyridine)copper(II) triflate borohydride DCM = dichloromethane NaH = sodium hydride DMA = N,N-dimethylacetamide NHP = non-human primate DMF = N,N-dimethylformamide PBS = phosphate buffered saline DMSO = dimethyl sulfoxide Pd / C = palladium on carbon Et2O = diethyl ether PPh3 = triphenylphosphine EtOAc = ethyl acetate RT = room temperature EtOH = ethanol SUV = standardized uptake volume HCl = hydrogen chloride TEA = triethylamine HPLC = high-performance liquid THF = tetrahydrofuran chromatography i.v. = intravenous TLC = thin liquid chromatography K222= kryptofix 222 tR= retention time K2CO3 = potassium carbonate VOI = volume of interest KOTf = potassium triflate General procedures A compound of general formula (I), wherein R1is18F can be synthesized by one of the following methods (Reaction Scheme 1): (II) (I) R2= CH3, CH(CH3)2,R3= CH3or C2H5,R2= CH3, CH(CH3)2Reaction Scheme 1 Boronic acid esters (a compound of general formula (II)) was used for the preparation of a compound of general formula (I), wherein R1is18F, in which process a copper(II)-mediated radiofluorination reaction was carried out, using preferably Cu(OTf)2(py)4, the fluorine-18 activity was recovered from the ion-exchange column with a potassium salt, preferably K2CO3 and KOTf, using a phase transfer catalyst, preferably K222, under heated reaction condition, preferably at 80-90oC, in a bipolar aprotic solvent, preferably in dry DMA, in a short reaction time, preferably 20 min (Tredwell et al., Angew. Chem. Int. Ed. 2014, 53(30):7751–55). A compound of general formula (I), wherein R2is11CH3,can be synthesized by one of the following methods (Reaction Scheme 2): A = CH or N A = CH or N Reaction Scheme 2 A compound of general formula (I), wherein R2is11CH3was produced via N-methylation of the secondary amine precursors (Garg et al., J. Nucl. Med.2017, 58(3):473-78; Zirsberger K et al. EJNMMI Radiopharm Chem. 2017, 2(10):1-12). It was a nucleophile alkylation step, using a [11C]alkylating agent, preferably [11C]MeOTf, and a mixture of bipolar aprotic solvents, preferably DMF and acetone, under low temperature, preferably at -5oC, in a short reaction time, preferably 2 min. The secondary amine precursors (III) are known in the art (WO 2016 / 166684 A1). A compound of general formula (II) can be synthesized by one of the following methods (Reaction Scheme 3): Reaction Scheme 3 The compound of formula (3) was obtained from compound of formula (1) [Reference Example 1 of WO2016 / 166684] by reacting the compound of formula (2) [Example 1, step (2) in EP1741703] in step (i): in the presence of a catalyst, preferably copper(I) iodide, a base, preferably Cs2CO3, a ligand, preferably trans-N,N’-dimethylcyclohexan-1,2-diamine, under heated reaction conditions, preferably at 110oC, in an inert solvent, preferably in toluene under Ar. The intermediate of formula (4) was prepared from compound of formula (3) via step (ii) in a debenzylation step, preferably in the presence of a hydrogen gas, a catalyst, preferably Pd / C, under acidic conditions, preferably AcOH in MeOH at RT. The compound of formula (6) was synthesized from compound of formula (4) with a suitable benzyl bromide derivative (compound of formula 5) in the following step (iii): in the presence a base, preferably NaH, under normal reaction conditions, preferably at RT, in an inert solvent, preferably in DMF under Ar. The compound of formula (7) was prepared from the compound of formula (6) via step (iv) in a deprotection step, preferably using HCl in EtOAc at RT. A precursor compound of general formula (II) was obtained from the compound of formula (7). When R2is CH3group in a compound of general formula (II), aqueous formaldehyde solution was used with NaBH(OAc)3 in a mixture of MeOH and DCM solvent in step (v). When R2is CH(CH3)2 group in a compound of general formula (II), an alkylating agent was used, preferably 2- iodopropane, a base, preferably K2CO3, under heated reaction condition, preferably at 80oC, in a bipolar aprotic solvent, preferably in CH3CN (step (vi)). In an alternative synthetic pathway, a precursor compound of general formula (II) was obtained from the compound of formula (11) according to step (iii). The compound of formula (11) was prepared from compound of formula (10) via debenzylation step according to step (ii). The compound of formula (10) was obtained from compound of formula (9) reacting compound of formula (2) via step (i). The compound of formula (9) was obtained from compound of formula (8) according to step (v) or (vi). The compound of formula (8) was prepared from compound of formula (1) in a deprotection step according to step (iv). Reference Example 1 was originally synthesized by carrying out a Mitsunobu synthesis with a 4-hydroxy-pyridinone intermediate (12) and a 4-fluoro-benzylalcohole (13) (Haga et al., Bioorg Med Chem 2011, 19:883-93; Reaction Scheme 4). 12 13 Reference example 1         TC‐MCH 7cReaction Scheme 4 In our modified method the key intermediate was a 4-bromo-pyridinone derivative (14). It was a common starting material for the preparation of Reference Example 1 and the boronic acid ester precursor Reference Example 2 (Reaction Scheme 5). In an alkylation step the compound of formula (14) was reacted with the suitable benzyl alcohol (15 or 16) in step (iii): in the presence of a base, preferably NaH, under heated reaction conditions, preferably at 100oC, in a bipolar aprotic solvent, preferably in anhydrous DMF, under Ar. Reference Example 3, as a reference PET ligand, was synthesized from the precursor Reference Example 2, according to a slightly modified method described in Reaction Scheme 1 (at 110oC for 13 min). Reference Example 3 [18F]TC-MCH 7cReaction Scheme 5 EXAMPLES In the present invention both TC-MCH 7c and [18F]TC-MCH 7c were synthesized via new synthetic pathways and investigated as Reference Examples 1 and 3. Reference Example 1 4-[(4-fluorophenyl)methoxy]-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}pyridin-2(1H)-one The title compound was described in Example 29 of WO2005 / 085200. It was prepared according to a different synthetic route and isolated without chromatography in the last step as follows. a.) 4-bromo-1-{4-[(tert-butyldimethylsilyl)oxy]phenyl}-1,2-dihydropyridin-2-one A mixture of 0.89 g (5.16 mmol) 4-bromopyridin-2(1H)-one, 3.9 g (15.47 mmol) of 4-(tert-butyldimethylsilyloxy)phenylboronic acid, 1.41 g (7.77 mmol) of Cu(OAc)2, 1.25 mL (15.47 mmol) of pyridine and 2.0 g (4Å) of molecular sieves in 40 mL DCM was stirred at RT for 72h. The mixture was filtered and washed with 100 mL of brine. The organic fraction was dried over MgSO4and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane / EtOAc, gradient from 10:1 to 1:1) and crystallized from cyclohexane to give 0.82 g (41%) 4-bromo-1-{4-[(tert- butyldimethyl-silyl)oxy]phenyl}-1,2-dihydropyridin-2-one as a pale-yellow solid . MS (ESI): [M+H]+= 380.1H NMR (400 MHz, DMSO) δ 7.62 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.81 (d, J = 2.2 Hz, 1H), 6.51 (dd, J = 7.3, 2.2 Hz, 1H), 0.97 – 0.89 (m, 1H), 0.97 (s, 9H), 0.25 – 0.21 (m, 6H).13C NMR (101 MHz, DMSO) δ: 160.0, 154.9, 139.8, 135.3, 133.4, 127.9, 121.9, 119.9, 109.2, 25.4, 17.8, -4.7. b.) 4-Bromo-1-(4-hydroxyphenyl)pyridin-2(1H)-one A mixture of 2.64 g (6.94 mmol) of 4-bromo-1-{4-[(tert-butyldimethyl-silyl)oxy]phenyl}- 1,2-dihydropyridin-2-one [Reference Example 1, step (a)] and 90 mL (83.3 mmol) 1M solution in THF of tetrabutylammonium fluoride was stirred at RT under Ar atmosphere overnight. After removal of the solvent, the residue was partitioned between water and EtOAc. The organic fraction was washed with 100 mL brine, dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was filtered through a short pad of silica gel with cyclohexane / EtOAc 1:3 solution as eluent. After evaporation of the solvent, the crude product was crystallized from Et2O to give 1.77 g (95.8%) 4-bromo-1-(4- hydroxyphenyl)pyridin-2(1H)-one as a pale-yellow solid. MS (ESI): [M+H]+= 266.1H NMR (500 MHz, DMSO) δ 9.79 (s, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.24 – 7.13 (m, 2H), 6.95 – 6.82 (m, 2H), 6.79 (d, J = 2.1 Hz, 1H), 6.49 (dd, J = 7.3, 2.2 Hz, 1H).13C NMR (126 MHz, DMSO) δ: 160.1, 157.2, 139.9, 135.2, 131.3, 127.6, 121.8, 115.3, 109.0. c.) 4-Bromo-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}pyridine-2(1H)-one To a solution of 1.22 g (4.58 mmol) 4-bromo-1-(4-hydroxyphenyl)pyridin-2(1H)-one [Reference Example 1, step (b)], 1.8 g (6.88 mmol) of PPh3and 0.65 mL (5.50 mmol) of 1- pyrrolidineethanol in 25 mL of THF was added 1.0 mL (6.88 mmol) of diethyl azodicarboxylate. The mixture was stirred at RT overnight and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM / MeOH, gradient from 10:1 to 1:10) and crystallized from Et2O to give 1.27 g (76%) of 4-bromo-1- {4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}pyridine-2(1H)-one as a white solid. MS (ESI): [M+H]+= 363.1H NMR (500 MHz, DMSO) δ 7.61 (d, J = 7.3 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.07 – 7.02 (m, 2H), 6.81 (d, J = 2.0 Hz, 1H), 6.51 (dd, J = 7.3, 2.2 Hz, 1H), 4.12 (t, J = 5.8 Hz, 2H), 2.90 – 2.75 (m, 2H), 2.64 – 2.52 (m, 4H), 1.70 (m, 2H).13C NMR (126 MHz, DMSO) δ: 160.1, 158.1, 139.8, 135.3, 132.7, 127.7, 121.9, 114.6, 109.1, 66.8, 54.0, 53.9, 23.0. d.) 4-[(4-fluorophenyl)methoxy]-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-1,2- dihydropyridin-2-one Into a 3-necked 25 mL flask, 0.071 g (1.79 mmol) of 60% NaH dispersion was added and suspended in 10 mL of anhydrous DMF under Ar atmosphere. The suspension was cooled to 0°C and 0.188 mL (1.79 mmol) of 4-fluorobenzyl alcohol was added. The mixture was stirred at 0°C for 10 min, then 0.5 g (1.38 mmol) of 4-bromo-1-{4-[2-(pyrrolidin-1-yl)ethoxy] phenyl}pyridine-2(1H)-one [Reference Example 1, step (c)] was added and the mixture was heated to 100°C for 15 min. Based on TLC (DCM / MeOH 1:1) and LC-MS analysis full conversion was achieved. The mixture was cooled and quenched with 10 mL of water and extracted with 3 x 3 mL of EtOAc. The organic fraction was washed with brine, dried over MgSO4and the solvent was evaporated under reduced pressure. The solid residue was crystallized from Et2O to give 0.178 g (32%) of 4-[(4-fluorophenyl)methoxy]-1-{4-[2- (pyrrolidin-1-yl)ethoxy]phenyl}-1,2-dihydro-pyridin-2-one as a white solid. MS (ESI): [M+H]+= 409.1H NMR (400 MHz, DMSO) δ 7.56 – 7.48 (m, 3H), 7.28 – 7.21 (m, 4H), 7.02 (d, J = 8.0 Hz, 2H), 6.06 (dd, J = 7.6, 2.7 Hz, 1H), 5.96 (d, J = 2.8 Hz, 1H), 5.11 (s, 2H), 4.10 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H), 2.55 – 2.52 (m, 3H), 1.69 (dt, J = 6.8, 3.2 Hz, 4H).13C NMR (101 MHz, DMSO) δ 166.6, 162.5, 161.9 (d, J = 244.2 Hz), 157.7, 139.2, 133.2, 132.0 (d, J = 3.0 Hz), 130.2 (d, J = 8.4 Hz), 127.9, 115.3 (d, J = 21.4 Hz), 114.5, 99.9, 97.7, 68.8, 67.0, 54.1, 53.86, 23.0.19F NMR (376 MHz, DMSO) δ -113.89 (tt, J = 9.0, 5.5 Hz).  Reference Example 2 1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]methoxy}pyridin-2(1H)-one Into a 3-necked 25 mL flask, 0.215 g (5.37 mmol) of 60% NaH dispersion was added and suspended in 15 mL of anhydrous DMF under Ar atmosphere. The suspension was cooled to 0°C and 1.17 mL (5.37 mmol) of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methanol was added. The mixture was stirred at 0°C for 10 min, then 1.5 g (4.13 mmol) of 4-bromo-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}pyridine-2(1H)-one [Reference Example 1, step (c)] was added and the mixture was heated to 100°C for 1 h. Based on LC-MS analysis full conversion was achieved, but formation of des-esterification side product (4-{[(2-oxo-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-1,2-dihydropyridin-4- yl)oxy]methyl}phenyl)boronic acid also was observed. The mixture was cooled and quenched with 30 mL of water and extracted with 3 x 10 mL of EtOAc. The organic fraction was washed with brine, dried over MgSO4 and the solvent was evaporated under reduced pressure. The solid residue was subjected to column chromatography on silica gel (CHCl3 / MeOH 10:1) and crude product crystallized from Et2O to give 0.298 g (14%) of 1-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}- 1,2-dihydropyridin-2-one as a white solid. MS (ESI): [M+H]+= 517.1H NMR (500 MHz, DMSO) δ 7.72 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.27 – 7.17 (m, 2H), 7.10 – 6.95 (m, 2H), 6.07 (dd, J = 7.6, 2.7 Hz, 1H), 5.93 (d, J = 2.7 Hz, 1H), 5.17 (s, 2H), 4.10 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H), 2.53 (br s, 4H), 1.69 (s, 4H), 1.30 (s, 12H).13C NMR (126 MHz, DMSO) δ: 166.6, 162.4, 157.7, 139.2, 139.1, 134.5, 133.2, 127.9, 127.8, 126.9, 114.5, 114.4, 99.9, 97.8, 83.6, 69.3, 67.0, 54.1, 53.9, 24.6, 23.0. Reference Example 3 4-{[4-(18F)fluorophenyl]methoxy}-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl} 2(1H)-one Fluorine-18 produced in a Siemens Eclipse RD cyclotron was adsorbed onto the Oasis Max column (Waters) with 98% efficiency which was preactivated with 2 mL of 0.15M KHCO3solution followed 8 mL of Milli-Q water. Fluorine-18 was recovered from the anion exchange column by elution with a solution containing 805 mL of stock solution (which was prepared from 2.3 mg / mL K222 in MeCN) and 240 mL of aqueous solution (made from 9 mg of K2CO3 and 12 mg of KOTf in 10 mL ultrapure water). The eluate was dried between 85 and 125oC in a nitrogen stream with vacuum. In the reactor of a GE TRACERlab FXFDG system 5.2 mg (0.01 mol) of 1-{4-[2- (pyrrolidin-1-yl)ethoxy]phenyl}-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] methoxy} pyridin-2(1H)-one [Reference Example 2] and 6.8 mg (0.01 mol) Cu(OTf)2(py)4were dissolved in 0.8 mL of DMA. This mixture was evaporated and transferred into the18F- containing solution and kept at 110oC for 13 min. The reaction was quenched by addition of 1 mL of water at 40oC. HPLC purification was performed using Kromasil Eternity XT 10- C18 (10x150 mm) at a flow rate 5 mL / min; eluent Ethanol / citrate buffer (pH=6.4) (30:70) at RT with a 270 nm UV detector (tR = 12.3 min). Applying this condition, the radiochemical purity of the titled compound was 98.5 + 0.9% (n = 5), the molar radioactivity was 1065 + 365 GBq / mmol. For shaping of the radiolabeled product, 4 mL of the radioactive solution was filtered through a Millex sterile filter (0.22 ^m x 4mm), diluted 10 mL of PBS, adjusted the pH 6.5 with 1.6 mL of 1N NaOH solution, and ensured the resistance of the preparation to radiolysis with 1.5 mL 10% of sodium ascorbate solution. Non-radioactive compounds Example 1 4-[(4-fluorophenyl)methoxy]-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a] indol-9- 2(1H)-one The title compound and its synthesis were described in Example 21 of WO2016 / 166684. MS (ESI): 446.2 [M+H]+.1H NMR (400 MHz, DMSO) δ: 7.55 – 7.50 (m, 3H), 7.47 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.29 – 7.23 (m, 2H), 6.96 (dd, J = 8.7, 2.1 Hz, 1H), 6.27 (s, 1H), 6.05 (dd, J = 7.6, 2.7 Hz, 1H), 5.96 (d, J = 2.7 Hz, 1H), 5.12 (s, 2H), 4.30 (d, J = 7.1 Hz, 2H), 3.05 – 2.96 (m, 3H), 2.73 – 2.62 (m, 4H), 0.99 (d, J = 6.6 Hz, 6H).13C NMR (101 MHz, DMSO) δ: 166.5, 162.8, 162.2 (d, J = 244.1 Hz), 143.7, 139.82 (s), 135.51 (s), 132.44 (s), 132.1 (d, J = 3.1 Hz), 130.2 (d, J = 8.3 Hz), 127.0, 119.0, 117.5, 115.3 (d, J = 21.4 Hz), 109.0, 99.5, 99.0, 97.7, 68.8, 55.6, 51.9, 50.8, 45.7, 29.5, 17.9 (s).19F NMR (376 MHz, DMSO) δ -113.91 (dq, J = 9.1, 5.5 Hz). Example 2 4-[(4-Fluorophenyl)methoxy]-1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7- a]indol-9-yl)pyridin-2(1H)-one a.) 9-bromo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole hydrochloride To a solution of 5.35 g (14.7 mmol) of tert-butyl 9-bromo-1,2,4,5-tetrahydro-3H- [1,4]diazepino[1,7-a]indole-3-carboxylate [Reference Example 1 of WO2016 / 166684] in 73 mL of EtOAc, 50 mL of 20% HCl in EtOAc was added. The mixture was stirred at RT. After 3 hours, the solid product was filtered, washed with 3 x 15 mL of EtOAc, then dried to obtain 4.42 g (99%) pale-grey crystals of 9-bromo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7- a]indole hydrochloride MS (ESI): 265.0 [M+H]+. b.) 9-bromo-3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole 4.42 g (14.7 mmol) of 9-bromo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole hydrochloride [Example 1, step (a)] was suspended in the mixture of 300 mL DCM and 200 mL MeOH.2.92 mL (39.2 mmol) of 37% aqueous formaldehyde solution was added in one portion. The suspension was cooled to 0 °C and 11.5 g (54.2 mmol) of NaBH(OAc)3 was added in one portion. The cooling bath was removed, and the reaction mixture was allowed to heat to RT. Then, 10 mL of water was added, and the organic solvents were evaporated. 100 mL of DCM was added, and the mixture was basified with saturated Na2CO3 solution. The phases were separated, then the organic phase was washed with 2 x 20 mL of brine, dried over anhydrous MgSO4, filtered and concentrated in vacuum.3.28 g (80%) of blueish crystals of 9-bromo-3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole was obtained, no further purification was needed. MS (ESI): 279.0 [M+H]+. c.) 4-[(4-fluorophenyl)methoxy]-1-(3-methyl-2,3,4,5-tetrahydro-1H- diazepino[1,7-a] indol-9-yl)pyridin-2(1H)-one The mixture of 300 mg (1.1 mmol) of 9-bromo-3-methyl-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indole [Example 2, step (b)], 259 mg (1.2 mmol) of 4-[(4-fluorophenyl) methoxy]-1,2-dihydropyridin-2-one [WO2007018248, Reference Example 2], 490 mg (1.5 mmol) of Cs2CO3, 168 mg (1.2 mmol) of trans-N,N'-dimethylcyclohexan-1,2-diamine and 50 mL of toluene were stirred at RT for 1h while Ar was bubbled through the mixture.225 mg (1.2 mmol) of copper(I) iodide was added to the mixture, immersed into an oil bath of 110° C and the mixture was stirred overnight at this temperature under Ar atmosphere. The mixture was evaporated to dryness, taken up in 50 mL of DCM and washed with 30 mL of 14% ammonia solution. The inorganic phase was extracted with 2 x 10 mL of DCM, then the combined organic phase was washed with 3 x 20 mL of 14% ammonia solution, 2 x 20 mL of brine, dried over anhydrous MgSO4, filtered and concentrated in vacuum. The obtained 480 mg of brownish solid was triturated with 5 mL of EtOAc, filtered, washed with 2 x 3 mL of EtOAc, and dried to obtain 315 mg (70%) of the title compound. MS (ESI): 418.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) d: 7.57 – 7.51 (m, 3H), 7.48 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.29 – 7.22 (m, 2H), 6.96 (dd, J = 8.7, 2.1 Hz, 1H), 6.28 (s, 1H), 6.05 (dd, J = 7.6, 2.8 Hz, 1H), 5.96 (d, J = 2.7 Hz, 1H), 5.12 (s, 2H), 4.38 – 4.29 (m, 2H), 3.06 – 3.01 (m, 2H), 2.66-2-56 (m, 4H), 2.35 (s, 3H).13C NMR (100 MHz, DMSO-d6) d: 166.5, 162.8, 161.8 (d, J = 244.0 Hz), 143.4, 139.8, 135.5, 132.5, 132.1 (d, J = 3.0 Hz), 130.2 (d, J = 8.4 Hz), 127.0, 119.1, 117.5, 115.3 (d, J = 21.5 Hz), 109.0, 99.5, 99.1, 97.7, 68.8, 58.0, 56.8, 46.5, 44.1, 28.1.19F NMR (376 MHz, DMSO-d6) d: -113.9 (tt, J = 9.1, 5.5 Hz). Example 3 4-[(5-fluoropyridin-2-yl)methoxy]-1-(3-methyl-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one maleic acid salt The synthesis and analytical characterization of the title compound were described in Example 9 of WO2016 / 166684. Synthesis of18F precursors Example 4 1-[3-(Propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl]-4-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyridin-2(1H)-one a) 9-bromo-3-(propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole A mixture of 7.95 g (26.4 mmol) 9-bromo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7- a]indole hydrochloride [Example 2, step (a)], 105 mL of acetonitrile, 16.40 g (119 mmol) of K2CO3and 14.7 mL (145 mmol) of 2-iodopropane was stirred at reflux temperature for 16 h. After cooling to RT, the mixture was filtered through a short pad of Celite, the solution was evaporated to dryness. The residue was partitioned between 50 mL of DCM – 50 mL of water, the phases were separated. The inorganic phase was extracted with 2 x 20 mL of DCM, then the combined organic phase was washed with 2 x 20 mL of brine, dried over anhydrous MgSO4, filtered and concentrated in vacuum to obtain 7.69 g (95%) of 9-bromo-3-(propan- 2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole as greenish solid product. MS (ESI): 307.1 [M+H]+. b.) 4-(benzyloxy)-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9- yl]pyridine-2(1H)-one The mixture of 7.69 g (25 mmol) of 9-bromo-3-(propan-2-yl)-2,3,4,5-tetrahydro-1H- [1,4]diazepino [1,7-a]indole [Example 4, step (a)], 5.54 g (27.5 mmol) of 4-(benzyloxy)-1,2- dihydropyridin-2-one [WO2005085200, Example 1], 11.0 g (33.8 mmol) of Cs2CO3, 3.92 g (27.5 mmol) of trans-N,N’-dimethylcyclohexan-1,2-diamine and 250 mL of toluene were stirred at RT for 1h while Ar was bubbled through the mixture. 5.24 g (27.5 mmol) of copper(I) iodide was added to the mixture, immersed into an oil bath of 110° C and the mixture was stirred overnight at this temperature under Ar atmosphere. The mixture was evaporated to dryness, taken up in 150 mL of DCM and stirred vigorously with 100 mL of 14 % ammonia solution. The phases were separated, the organic phase was washed with 5 x 30 mL of 14 % ammonia solution, 2 x 30 mL of brine, dried over anhydrous MgSO4, filtered and concentrated in vacuum. The obtained 11.5 g of greenish white solid was triturated with 35 ml EtOAc, cooled to 0 °C, filtered, washed with 10 mL of ice-cold EtOAc and dried to obtain 10.0 g (94%) of 4-(benzyloxy)-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7- a]indol-9-yl]pyridine-2(1H)-one as an off-white solid. MS (ESI): 428.4 [M+H]+. c) 4-hydroxy-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9- yl]pyridine-2(1H)-one In a 3-necked 250ml flask, 10 g (23.4 mmol) of 4-(benzyloxy)-1-[3-(propan-2-yl)- 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl]pyridine-2(1H)-one [Example 4, step (b)] was suspended in 150 mL of MeOH. 6.69 mL (117 mmol) of AcOH was added to the suspension, which turned into a dark green solution. After a few min, some precipitate formed in the solution. Ar was bubbled through the mixture for 30 min, then 4.98 g (4.7 mmol) of 10% Pd / C catalyst was added. After 10 min, the Ar bubbling was exchanged to hydrogen gas. After 90 min hydrogenation, the mixture was flushed with Ar, then the suspension was filtered through a short pad of Celite, washed with 80 mL of DCM and the solution was evaporated to dryness to gain an off-white solid. The residue was suspended in 100 mL of DCM and 23 mL (164 mmol) of TEA was added.100 mL of MeCN was added to the clear solution. After evaporating most of the DCM from the solution, slow precipitation of the product could be observed. The mixture was stirred overnight at RT. The off-white precipitate was filtered to yield 4.81 g (61%) of 4-hydroxy-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diaze- pino[1,7-a]indol-9-yl]pyridine-2(1H)-one. MS (ESI): 338.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) d: 7.43 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 6.94 (dt, J = 7.2, 3.6 Hz, 1H), 6.25 (s, 1H), 5.86 (dd, J = 7.5, 2.6 Hz, 1H), 5.51 (d, J = 2.5 Hz, 1H), 4.29 (d, J = 4.4 Hz, 2H), 3.03 – 2.95 (m, 3H), 2.68 (t, J = 9.2 Hz, 4H), 0.99 (d, J = 6.6 Hz, 6H).13C NMR (101 MHz, DMSO-d6) d: 168.8, 163.2, 143.5, 139.5, 135.3, 133.1, 127.0, 119.3, 117.5, 108.8, 101.0, 99.0, 98.1, 55.6, 51.9, 50.8, 45.6, 29.5, 17.9. d.) 1-[3-(Propan-2-yl)-2,3,4,5-tetrahydro- diazepino[1,7-a]indol-9-yl]-4-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- methoxy}pyridin-2(1H)-one Into a 3-necked 100 mL flask, 277 mg (6.9 mmol) of 60% NaH dispersion was added and suspended in 27 mL of anhydrous DMF under Ar atmosphere. The suspension was cooled to 0 °C and 1.80 g (5.3 mmol) of 4-hydroxy-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl pyridin-2(1H)-one [Example 4, step (c)] was added in one portion. After stirring the mixture 5 min at 0 °C, 2.17 g (6.9 mmol) of 2-[4- (bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added to the mixture. The suspension was allowed to heat to RT and stirred 3 h. Then, the suspension was cooled to 0 °C, and 20 mL of water was added. The temperature raised to 25 °C and the dense suspension became difficult to stir. The solid was filtered, washed with 3 x 10 mL of water, 3 x 10 mL of Et2O. The off-white solid was dried to mass consistency, then triturated with 1 x 40 mL of MeCN. The solid was dried to mass consistency, to obtain 1.23 g (42%) of the title compound as an off-white solid with 91% content determined with quantitative1H-NMR. Due to the hydrolytic instability of the boronic ester moiety, the product could not be purified further with chromatography, it was ready for the18F radioligand synthesis. MS (ESI): 554.3 [M+H]+.1H NMR (400 MHz, CDCl3) δ: 7.85 (d, J = 8.0 Hz, 2H), 7.45 – 7.39 (m, 3H), 7.30 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.09 (dd, J = 8.6, 2.0 Hz, 1H), 6.27 (s, 1H), 6.07 (d, J = 2.7 Hz, 1H), 6.03 (dd, J = 7.5, 2.7 Hz, 1H), 5.06 (s, 2H), 4.29 – 4.24 (m, 2H), 3.10 – 2.95 (m, 3H), 2.80 – 2.69 (m, 4H), 1.36 (s, 12H), 1.05 (d, J = 6.6 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 167.3, 164.7, 144.0, 139.1, 138.5, 136.3, 135.3, 132.9, 129.3 (HMBC), 128.1, 127.0, 119.4, 118.1, 109.0, 100.8, 99.8, 98.8, 84.0, 70.2, 56.7, 52.3, 51.4, 46.4, 30.4, 25.0, 18.4. Example 5 1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)-4-{[4-(4,4,5,5- tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyridin-2(1H)-one a.) tert-butyl 9-(4-hydroxy-2-oxopyridin-1(2H)-yl)-1,2,4,5-tetrahydro-3H-[1,4]diazepino [1,7-a]indole-3-carboxylate In a 3-necked 100 ml flask, 960 mg (1.98 mmol) of tert-butyl 9-[4-(benzyloxy)-2- oxopyridin-1(2H)-yl]-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate [WO2016 / 166684, Reference Example 6] was suspended in 20 mL of MeOH. After adding 30 mL of DCM, Ar was bubbled through the solution for 30 min, then 316 mg (0.297 mmol) 10% Pd / C catalyst was added. After 10 min, the Ar bubbling was exchanged to hydrogen gas. After 3 h hydrogenation, the mixture was flushed with Ar, then the suspension was filtered through a short pad of Celite, washed with 30 mL of DCM and the solution was evaporated to dryness to gain a brownish solid. The residue was triturated in 10 mL of MeCN, filtered, and washed with 2 x 5 mL of MeCN. The off-white precipitate was filtered to yield 650 mg (83%) of tert-butyl 9-(4-hydroxy-2-oxopyridin-1(2H)-yl)-1,2,4,5-tetrahydro-3H- [1,4]diazepino [1,7-a]indole-3-carboxylate. MS (ESI): 396.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) d:10.65 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 7.4 Hz,1H), 7.35 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.7, 2.0 Hz, 1H), 6.32 (s, 1H), 5.93 (dd, J = 7.5, 2.6 Hz, 1H), 5.64 (d, J = 2.6 Hz, 1H), 4.37 – 4.31 (m, 2H), 3.65 – 3.62 (m, 2H), 3.58 – 3.54 (m, 2H), 3.05 (d, J = 3.8 Hz, 2H), 1.46 (s, 9H).13C NMR (101 MHz, DMSO-d6) d: 166.5, 162.9, 154.0, 142.3, 140.1, 136.0, 132.9, 127.0, 119.5, 117.5, 109.2, 100.5, 99.6, 98.4, 79.2, 47.3 (br), 46.0 (br), 45.73 (br), 29.4(br), 28.0. b.) 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetraethyl-1,3,2-dioxaborolane In a one-necked 100 mL flask, 933 mg (5.4 mmol) of 3,4-diethylhexane-3,4-diol was dissolved in 53 mL of DCM. To this solution 1.15 g (5.35 mmol) of [4-(bromo- methyl)phenyl]boronic acid and 1.93 g (16.1 mmol) of anhydrous Na2SO4 were added, respectively. The mixture was stirred at RT for 48h. Then, the inorganic impurities were removed by filtration, the filtrate was evaporated to dryness. The crude product was purified with flash chromatography using c-hexane-EtOAc 96:4 to obtain 1.57 g (83%) of 2-[4- (bromomethyl)phenyl]-4,4,5,5-tetraethyl-1,3,2-dioxaboro-lane as a clear oil.1H NMR (400 MHz, DMSO-d6) δ: 7.68 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 4.71 (s, 2H), 1.76 – 1.65 (m, 8H), 0.91 (t, J= 7.4 Hz, 12H)13C NMR (101 MHz, DMSO-d6) δ: 141.1, 134.6, 128.63, 88.4, 34.0, 25.9, 8.54. c.) tert-butyl 9-[2-oxo-4-{[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy} pyridin-1(2H)-yl]-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate Into a 3-necked 100 mL flask, 79 mg (2 mmol) of 60% NaH dispersion was added and suspended in 24 mL of anhydrous DMF under Ar atmosphere. The suspension was cooled to 0 °C and 600 mg (1.5 mmol) of tert-butyl 9-(4-hydroxy-2-oxopyridin-1(2H)-yl)-1,2,4,5- tetrahydro-3H-[1,4]diazepino [1,7-a]indole-3-carboxylate [Example 5, step (a)] was added. After stirring 10 min at 0 °C, 789 mg (2.1 mmol) of 2-[4-(bromomethyl)phenyl]-4,4,5,5- tetraethyl-1,3,2-dioxaborolane [Example 5, step (b)] was added in one portion. The solution was allowed to heat to RT and stirred 2 h. The reaction was quenched with 500 µL of water, then 3 mL of 10 % citric acid and 21 mL of water was added. The gummy solid residue was filtered, washed with 10 mL of water. The solid was redissolved in 30 mL of DCM, dried over anhydrous Na2SO4, filtered and evaporated to dryness. The crude product was purified with flash chromatography using c-hexane-EtOAc 1:1 to obtain 473 mg (47%) of the title compound. MS (ESI): 668.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 7.74 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 6.3 Hz, 1H), 7.47 (s, 2H), 7.37 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 8.7, 2.0 Hz, 1H), 6.33 (s, 1H), 6.07 (dd, J = 7.6, 2.7 Hz, 1H), 5.93 (d, J = 2.7 Hz, 1H), 5.18 (s, 2H), 4.35 (m, 2H), 3.64 (m, 2H), 3.56 (m, 2H), 3.06 (m, 2H), 1.78 – 1.67 (m, 8H), 1.46 (s, 9H), 0.93 (t, J = 7.4 Hz, 12H).13C NMR (101 MHz, DMSO-d6) δ: 166.5, 162.8, 154.0 (HMBC), 142.4, 139.8, 139.2, 136.0, 134.5, 132.6, 127.1 (HMBC), 127.0, 126.9, 119.4, 117.5, 109.3, 100.5, 99.5, 97.8, 88.3, 79.2, 69.2, 47.2 (HSQC), 46.0 (HSQC), 45.7 (HSQC), 29.5 (HSQC), 28.0, 26.0, 8.6. d.) 4-{[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}-1-(2,3,4,5- tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one hydrochloride salt H Cl Into a one-necked 100 mL flask 430 mg (0.64 mmol) of tert-butyl 9-[2-oxo-4-{[4- (4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyridin-1(2H)-yl]-1,2,4,5- tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate [Example 5, step (c)] was suspended in 30 mL of EtOH. Then, 10 mL of DCM was added when the suspension turned into clear solution.12 mL of 20 % HCl in EtOAc was added. The mixture was stirred at RT overnight, then evaporated to dryness to obtain the title compound as off-white crystals, assuming quantitative yield and was taken to the next step without further purification. MS (ESI): 568.4 [M+H]+. e.) 1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)-4-{[4-(4,4,5,5- tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyridin-2(1H)-one In a 3-necked 100 mL flask, 389 mg (0.64 mmol) of 4-{[4-(4,4,5,5-tetraethyl-1,3,2- dioxa-borolan-2-yl)phenyl]methoxy}-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol- 9-yl)pyridin-2(1H)-one hydrochloride salt [Example 5, step (d)] was added and dissolved in the mixture of 13 mL of DCM and 8 mL of MeOH. Then 128 µL (1.72 mmol) of 37% aqueous formaldehyde solution was added and the solution was cooled to 0 °C.504 mg (2.38 mmol) of NaBH(OAc)3 was added and the mixture was allowed to heat to room temperature. Based on TLC (EtOAc / MEOH / TEA 50:10:5), full conversion was not achieved, so another portion of NaBH(OAc)3(164 mg, 0.77 mmol) was added at 0 °C. After 5 min, the reaction was quenched at 0 °C with 3 mL of water. The mixture was diluted with 25 mL of DCM, the organic phase was washed with 10 mL of saturated NaHCO3-solution, 2 x 10 mL of brine, dried over anhydrous Na2SO4, filtered and evaporated to dryness to yield 360 mg (96% for last 2 steps) of the title compound as white crystals. MS (ESI): 582.4 [M+H]+.1H NMR (400 MHz, DMSO) d: 7.74 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.50 – 7.46 (m, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.7, 2.1 Hz, 1H), 6.27 (s, 1H), 6.06 (dd, J = 7.6, 2.7 Hz, 1H), 5.93 (d, J = 2.7 Hz, 1H), 5.18 (s, 2H), 4.33 (m, 2H), 3.06 – 3.00 (m, 2H), 2.59 (m, 4H), 2.35 (s, 3H), 1.79 – 1.64 (m, 8H), 0.93 (t, J = 7.4 Hz, 12H).13C NMR (101 MHz, DMSO) d: 166.46, 162.8, 143.4, 139.8, 139.2), 135.5, 134.5, 132.5, 128.0 (HMBC), 127.0, 119.1, 117.5, 109.0, 99.5, 99.0, 97.8, 88.3, 69.2, 58.0, 56.8, 46.5, 44.1, 28.1, 26.0, 8.6. Synthesis of11C precursors Example 6 4-[(4-fluorophenyl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9- yl)pyridin-2(1H)-one maleate salt In a one-necked 50 mL flask, 252 mg (0.625 mmol) of 4-[(4-fluorophenyl)methoxy]- 1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one [Example 5, step (a) of WO2016 / 166684], was dissolved in 5 mL of DCM. Then, the solution of 72.5 mg (0.625 mmol) maleic acid in 625 µL of MeOH was added to the mixture. White precipitation formed instantly; the suspension was stirred at RT for 5 min. The crystals were filtered, washed successively with 2 x 2 mL of DCM-MeOH 1:1, 2 x 5 mL of Et2O and dried to obtain 220 mg (68%) of the title compound. MS (ESI): 404.2 [M+H]+.1H NMR (400 MHz, DMSO) δ: 8.93 (bs, 2H), 7.57 – 7.50 (m, 4H), 7.43 (d, J = 2.0 Hz, 1H), 7.29 – 7.23 (m, 2H), 7.05 (dd, J = 5.6, 3.1 Hz, 1H), 6.43 (s, 1H), 6.07 (dd, J = 7.6, 2.8 Hz, 1H), 6.02 (s, 2H), 5.96 (d, J = 2.7 Hz, 1H), 5.12 (s, 2H), 4.57 (d, J = 5.7 Hz, 2H), 3.40 – 3.22 (m, 6H),13C NMR (101 MHz, DMSO) δ: 167.0, 166.5, 162.8, 161.8 (d, J = 244.3 Hz), 140.5, 139.7, 135.9, 135.7, 133.0, 132.1 (d, J = 3.0 Hz), 130.2 (d, J = 8.4 Hz), 126.9, 119.9, 117.93, 115.3(d, J = 21.4 Hz), 109.4, 100.7, 99.6, 97.7, 68.8, 46.8, 45.5, 40.9, 24.6.19F NMR (376 MHz, DMSO) δ: -113.85 – - 113.93 (m). Salt equivalence: 1:1, based on1H NMR (400 MHz, DMSO), marker peaks: cation of the product 6.07 (dd, J = 7.6, 2.8 Hz, 1H), maleate ion: 6.02 (s, 2H). Example 7 4-[(5-fluoropyridin-2-yl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol- 9-yl)pyridin-2(1H)-one maleate salt In a one-necked 50 mL flask, 418 mg (1.03 mmol) of 4-[(5-fluoropyridin-2- yl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one [Example 1, step (a) of WO2016 / 166684] was dissolved in the mixture of 15 mL DCM and 3 mL of MeOH. Then, the solution of 120 mg (0.625 mmol) of maleic acid in 1 mL of MeOH was added to the mixture. After stirring for 5 mins at RT, the solution became cloudy.2 mL of Et2O was added, and the suspension was stirred for 20 min at RT. The off-white crystals were filtered, washed with 2 x 4 mL of Et2O, and dried to obtain 450 mg (84%) of the title compound. MS (ESI): 405.2 [M+H]+.1H NMR (400 MHz, DMSO) δ: 8.92 (bs, 2H), 8.62 (d, J = 2.9 Hz, 1H), 7.83 (td, J = 8.7, 3.0 Hz, 1H), 7.66 (dd, J = 8.7, 4.5 Hz, 1H), 7.54 (dd, J = 8.2, 4.5 Hz, 2H), 7.43 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 8.7, 2.1 Hz, 1H), 6.43 (s, 1H), 6.11 (dd, J = 7.6, 2.8 Hz, 1H), 6.11 (dd, J = 7.6, 2.8 Hz, 1H), 6.02 (s, 2H), 5.96 (d, J = 2.7 Hz, 1H), 5.21 (s, 2H), 4.56 (d, J = 4.9 Hz, 2H), 3.38-3.25 (m, 6H).13C NMR (101 MHz, DMSO) δ 167.0, 166.4, 162.7, 158.8 (d, J = 254.0 Hz), 151.7 (d, J = 3.8 Hz), 140.5, 139.8, 137.3 (d, J = 23.7 Hz), 136.0, 135.7, 132.9, 126.9, 123.9 (d, J = 18.5 Hz), 123.8 (d, J = 4.7 Hz), 119.8, 117.9, 109.4, 100.7, 99.5, 97.8, 69.8 (d, J = 1.2 Hz), 46.8, 45.5, 40.9, 24.6.19F NMR (376 MHz, DMSO) δ -128.02 (dd, J = 8.8, 4.5 Hz). Salt equivalence: 1:1, based on1H NMR (400 MHz, DMSO), marker peaks: cation of the product 6.11 (dd, J = 7.6, 2.8 Hz, 1H), maleate ion: 6.02 (s, 2H). Radiosynthesis Example 8 4-{[4-(18F)fluorophenyl]methoxy}-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl]pyridin-2(1H)-one According to the described method in Reference Example 3, the title compound was synthesized. 5.5 mg (0.01 mol) of 1-[3-(Propan-2-yl)-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl]-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxa-boro-lan-2- yl)phenyl]methoxy}pyridin-2(1H)-one [Example 4] and 6.8 ,g (0.01 mol) Cu(OTf)2(py)4were dissolved in 0.8 mL of DMA. This mixture was evaporated and transferred into the18F- containing solution and kept at 80oC for 20 min. The reaction was quenched by addition of 1 mL of water at 40oC. HPLC purification was performed using Waters, XBridge BEH Shield RP18 column (130 Å, 5 mm, 4.6x250 mm) at a flow rate 1.2 mL / min; eluent ‘A’= HCOOH / MeCN / H2O (1:100:900); eluent ‘B’= HCOOH / MeCN / H2O (1:900:100); conc. of ’B’ eluent=22% at RT with a 270 nm UV detector (tR= 11.2 min). Applying this condition, the radiochemical purity of the title compound was 98.3 + 0.4% (n = 7), the molar radioactivity was 2371 + 659 GBq / ^mol. For shaping of the radiolabeled product, 10 mL of the radioactive solution was filtered through a Millex sterile filter (0.22 mm x 4mm), diluted 6.5 mL of PBS, adjusted the pH 6.5 with 0.8 mL of 1N NaOH solution, and ensured the resistance of the preparation to radiolysis with 0.91 mL of sodium ascorbate (1:10). Example 9 4-{[4-(18F)fluorophenyl]methoxy}-1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl)pyridin-2(1H)-one The title compound was prepared from 1-(3-methyl-2,3,4,5-tetrahydro-1H- [1,4]diazepino [1,7-a]indol-9-yl)-4-{[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl] methoxy}pyridin-2(1H)-one [Example 5] in a copper(II)-mediated radio-fluorination reaction by a slightly modified method described in Example 8: the reaction time was 20 min at 90oC. HPLC flow rate was 3.2 mL / min; eluent ‘A’= citrate buffer(pH=3) / EtOH (1:1); eluent ‘B’= citrate buffer(pH=3) / EtOH (4:1); conc. of ’A’ eluent=40% -> 66%. Applying these conditions (n = 5), the radiochemical purity of the title compound was 99.8 + 0.12% (tR= 17 min), the molar radioactivity was 1122 + 248 GBq / ^mol. Example 10 4-[(4-fluorophenyl)methoxy]-1-[3-(11C)methyl-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl]pyridin-2(1H)-one [11C]CO2 was produced in a Siemens Eclipse RD cyclotron, which was reduced to firstly [11C]CH4, and further converted to [11C]CH3OTf by using a commercial radiochemistry platform (ScanSys). The [11C]CH3OTf gas was bubbled through a solution of 1 mg of 4-[(4-fluorophenyl) methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one maleate salt [Example 6] in 300 mL of dry DMF, and 5 mL of 5N NaOH solution in 200 mL of acetone at -5oC. After 2 min at RT the reaction was complete, the reaction mixture was loaded into the HPLC loop, and the desired title compound was isolated by using Akzo-Nobel Kromasyl EternityXT-C18 column (10 mm, 10x150 mm) eluted with 65% citrate buffer (pH: 6.2) and 35% EtOH at a flow rate 6 mL / min with a 254 nm UV detector (tR= 6.2 min). Applying these conditions, the radiochemical purity of the title compound was 98.3 + 1.3% (n = 3), the molar radioactivity was 75 + 9.3 GBq / ^mol. Example 11 4-[(5-fluoropyridin-2-yl)methoxy]-1-[3-(11C)methyl-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl]pyridin-2(1H)-one The title compound was prepared from 4-[(5-fluoropyridin-2-yl)methoxy]-1-(2,3,4,5- tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one maleate salt [Example 7] according to detailed procedure in Example 10. Applying this condition, the radiochemical purity (tR = 5.1 min) was 98.8 + 0.7% (n = 5), the molar radioactivity was 84.2 + 10.7 GBq / ^mol. In vitro binding assay at human MCH1 receptors using [125I] Tyr-S36057 as radioligand Membrane was prepared from the human recombinant CHO-K1 cells (PerkinElmer, cat# ES-370-M) steadily expressing the hMCHR1receptor. Receptor binding assays were performed in 10 concentrations, with two parallel samples in each concentration using an incubation buffer (25 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM EDTA, 0.2% BSA), cell membrane of CHO-K1 cells steadily expressing hMCHR1 receptor, 1% DMSO as vehicle and 0.05 nM [125I] Tyr-S36057 - as radioligand. Non-specific binding was determined in the presence of 1 μM MCH. Samples were incubated for 120 min at 25 °C. Binding reactions were terminated by rapid filtration and radioactivity was determined. Historical KD and historical Bmaxof the optimized saturation binding was 0.1 nM and 26.0 pmole / mg protein, respectively. Radioligand displacement by the test compounds were characterized by IC50values which were determined by a non-linear, least squares regression analysis using MathIQTM (ID Business Solutions Ltd., UK). Inhibition constants (Ki) are presented, the Ki values were calculated using the equation of Cheng and Prusoff (Cheng, Y., Prusoff, W. H., Biochem. Pharmacol. 1973, 22:3099-3108,) using the observed IC50of the tested compound, the concentration of radioligand employed in the assay, and the historical values for the KD (0.1 nM) of the radioligand (obtained experimentally at Eurofins Panlabs, Inc.). Hill coefficient (nH), defining the slope of the competitive binding curve, was calculated using MathIQTM(version 1.0). Hill coefficients significantly different than 1.0, may suggest that the binding displacement does not follow the laws of mass action with a single binding site. In vitro human binding data of the test compounds substantiate that Example 1-3 exhibit a high binding affinity towards MCHR1. The binding data of Reference Example 1 (TC-MCH 7c) was in good correlation with published data (Haga et al., Bioorg Med Chem 2011, 19:883-9) Ex vivo MCHR1 receptor occupancy in rat striatal homogenate ([3H]SNAP binding) Male Wistar rats weighing 190-210 g were used. Rats were purchased from Toxi-Coop (Budapest, Hungary). Animals arrived at the facility at least four days before the experiment. They were fed with commercial chow and received tap water ad libitum. The experimental animals were kept in a thermostatically controlled room at 24 ± 2 °C and at relative humidity of 50 ± 10% on a 12-h light / dark cycle (lights off from 6:00 PM to 6:00 AM). The rats received unlimited access to commercial pellet rat feed autoclaved at 105 °C and tap water throughout all experiments. All applicable international, national and / or institutional guidelines for the care and use of animals were followed. All procedures involving test animals were reviewed and approved by the Gedeon Richter (internal) Institutional Animal Care and Use Committee and were in accordance with the directive 2010 / 63 / EU of the European Parliament on the protection of animals used for scientific purposes. Animals were dosed by intravenous administration (i.v.) (2.5 mL / kg) in the tail vein with either vehicle (DMA in 25% HPβCD in distilled water) or 1 mg / kg dose of the four studied ligands in the same formulation. MCHR1 receptor occupancy was determined from 4 rats per dosing group. Decapitation and brain dissection took place 30 minutes after i.v. and 120 minutes after p.o. dosing and rat striatal tissue preparations were completed within a subsequent 5-minute time frame. Brain samples were rapidly frozen using dry ice and stored at -70 °C until use. Rat striatum was homogenized in 9 vol. (w / v) (15 mg wet tissue / tube) of assay buffer (50 mM Tris pH=7.4, 120 mM NaCl, 5 mM KCl, 1 mM MgCl2, 2.5 mM CaCl2), with an Ultra-Turrax tissue homogenizer (Setting 6, 10 s) at room temperature and the binding assay was performed immediately. Ex vivo [3H]SNAP-7941 binding assay was conducted in 1,2 mL deep well plates, (PS, non sterile, 96w, Izinta Kft.).40 μL striatal homogenate (15 mg wet tissue / mL) was incubated with 210 µL assay buffer and 50 µL 6 nM (1 nM in final assay concentration) [3H]SNAP- 7941(UBICHEM Research Ltd, Budapest, Hungary). Vehicle-treated control animals were used to determine non-specific binding (NSB) and total binding. Total binding assay volume was 400 µL. Incubations were carried out for 45 minutes at room temperature. Following the incubation, binding reactions were terminated by rapid filtration through a 96-well Filtermate Harvester (Perkin Elmer, Waltham, MA, USA) using UniFilter® GF / C (Perkin Elmer, Cat No.: 6055690) presoaked for at least 1 hour in 0.5% polyethylene imine (PEI, dissolved in distilled water). The filter plates were washed three times with 0.5 mL of ice-cold washing buffer (50 mM Tris, pH=7.4). Washed filter plates were dried at 40°C for 60 min and 40 µL of Microscint-20 (Perkin Elmer, Cat # 613621) scintillation cocktail was added to each well. Radioactivity was determined by Microbeta 2450-0060 Microplate Reader (Perkin Elmer) (software: MicroBeta2 Windows Workstation, version: 2.3.0.12; serial: 21210716). Specific radioligand binding is defined as the difference between total binding and the non-specific binding determined in the presence of an excess of unlabeled ligand. Ex vivo receptor binding of [3H]SNAP-7941 in the homogenates of drug-treated animals was measured and receptor occupancy by unlabeled compound administered in vivo was calculated and expressed as follows: Receptor occupancy (%) = 100×[1−(receptor labelling of drug-treated group / receptor labelling of vehicle-treated group)]. MCHR1 receptor occupancy was expressed as % inhibition of [3H]SNAP-7941 binding relative to vehicle control. Data presentation: values are mean percentage of occupancy ± SD. Ex vivo occupancy data of the test compounds characterize the binding profile of Example 1-3 by showing that not only high percentages of MCHR1 receptor population are occupied but an improved level of occupancy is evidenced when compared to Reference Example 1. On the basis of these data, there was no correlation in binding data and ex vivo occupancy of Refence Example 1. Table 1: In vitro human binding data and ex vivo occupancy in rat striatal homogenate Compound / PET ligand hMCHR1 Ex vivo occupancy (%) Ki (nM) rat, 1 mg / kg i.v. dose Example 1 / Example 8 9 96.8+2.0 Example 2 / Example 9 and 10 13 77.5+5.3 Example 3 / Example 11 33 71.5+3.7 Reference Example 1 / Ref. Ex.3 5.6 39.6+5.4   In vivo PET imaging in rats Experimental animals 16 weeks old, 256±10 g weighted male Wistar rats (n=16; Animalab Ltd, Budapest, Hungary) were used for the in vivo PET imaging and for the ex vivo experiments. Animals were housed under conventional conditions at 23±2°C with 50±10% humidity and artificial lighting with a circadian cycle of 12 h. The semi-synthetic diet (VRF1; Akronom Ltd., Budapest, Hungary) and drinking water were available ad libitum to all animals. The animal experiments were authorized by the Ethical Committee for Animal Research, University of Debrecen, Hungary. Laboratory animals were kept and treated in compliance with all applicable sections of the Hungarian Laws and animal welfare directions and regulations of the European Union. Permission number: III / 6-KÁT-2015. In vivo PET imaging of Example 8 Healthy control (n=16) Wistar rats were anaesthetized with 3% Forane (Forane, AbbVie) using a dedicated small animal anesthesia device (Tec3 Isoflurane Vaporizer, Eickemeyer Veterinary Equipment, UK). After the incubation time (20 min) pretreated rats were injected with 11.07±2.9 MBq of Example 8 in 150 μL saline via the lateral tail vein. Dynamic (0-180 min) PET scans were performed using the preclinical MiniPET-II device (Lajtos et al. Nuc. Int. Meth. in Phys. Res. A, 2013, 707:26-34). After 3D OSEM-LOR image reconstruction, volumes of interest (VOIs) were manually drawn around the whole brain using the Brain CAD image analysis software and quantitative standardized uptake values (SUVs) were calculated as follows: SUV = [VOI activity (Bq / mL)] / [injected activity (Bq) / animal weight (g)], assuming a density of 1 g / mL. For the determination of Example 8 in the brain, in vivo dynamic PET scans were performed under inhalation anesthesia. After the qualitative analysis of the decay-corrected images were identified till 40 min after the intravenous (i.v.) administration of Example 8 (Figure 2A). Analyzing the TAC data, continuous decreasing of the SUVmean values was observed in the brain (Figure 2B). PET images show, that Example 8 was able to cross the blood-brain barrier, and the concentration of the radioactivity decreased with time. During the dynamic PET scans, the radioligand was very stable in rat plasma, there weren’t observed any radio-metabolites. In vivo PET imaging of Example 9 and Example 10 Example 9 and Example 10, 11.07±2.9 MBq and 12.14±0.9 MBq in 150 μL saline injected respectively, were investigated via in vivo dynamic PET imaging according to the PET imaging method described with Example 8. Summarizing (0 -40 min) decay-corrected images and TAC curves were produced in both cases (Figure 3A and 3B, Figure 4A and 4B). Both fluorine-18 (Example 9) and the carbon-11 (Example 10) PET ligands entered the brain of healthy Wistar rats. In vivo PET imaging of Reference Example 3 For the determination of the MCHR receptor targeting potential of Reference Example 3 in the brain, in vivo dynamic PET scans were performed under inhalation anesthesia. After the qualitative analysis of the decay-corrected images we found that the significant radioactivity in the brain was not identifiable after the intravenous (i.v.) administration of the Reference Example 3 (Figure 5A, left). By analyzing the TAC data, continuous decreasing of the SUVmean values was observed in the brain (Figure 5B right upper). PET images show, that Reference Example 3 was not able to cross the blood-brain barrier. To investigate in vivo whether Reference Example 3 is a substrate for the P-glycoprotein (Pgp) of the blood-brain-barrier, experimental animals were pretreated intravenously with approximately 25 µg / bw g cyclosporin A (CSA). Ten minutes after the injection of CSA approx. 10 MBq of Reference Example 3 was injected via the lateral tail vein for PET imaging. As a result of CSA administration, a significantly higher brain accumulation was observed compared to the baseline, which suggests that Reference Example 3 can be the substrate of the Pgp pump (Figure 5A, right and Figure 5B right bottom). In vivo PET imaging of Example 11 Example 11 was investigated according to the PET imaging method conducted with Reference Example 3. The compound entered in the brain after a CSA pretreatment on healthy Wistar rats. Representative decay-corrected static PET images of the brain (0 – 40 min) without CSA pretreatment (Figure 6A, on the left) and with CSA pretreatment (Figure 6A, on the right). Recycles and arrows: brain (Figure 6A). Representative decay-corrected dynamic PET images and SUVmean time-activity curve (TAC) of Example 11 in the brain (Figure 6B). Ex vivo biodistribution in rats  Experimental animals Healthy control (n=16) Wistar rats were anaesthetized with 3% Forane (Forane, AbbVie) using a dedicated small animal anesthesia device (Tec3 Isoflurane Vaporizer, Eickemeyer Veterinary Equipment, UK). Ex vivo biodistribution of Example 8 For the determination of the normal biodistribution of Example 8, animals were injected with 11.26±2.08 MBq of Example 8 in 150 μL saline via the lateral tail vein.30 and 180 min after the injection of the Example 8 rats were euthanized with 5% Forane, dissected, and blood, urine, and samples were taken from selected organs. The weight and radioactivity of the selected organs and tissues were measured with a calibrated gamma counter (HEWLETT PACKARD Cobra II Autogama Gamma Counter). The uptake of Example 8 radiotracer was expressed as %ID / g tissue. Figure 7 shows the results of the biodistribution of Example 8. According to the data of imaging, the compound was excreted mainly through the liver of the investigated Wistar rats. In vivo PET imaging in non-human primates (NHP) All experimental procedures (except for housing and transportation) were conducted at the Medicopus facility in Kaposvár. The study was approved by the Local and National Ethical Committees on Animal Research and the Department of Animal Health and Food Control of the County Government Offices of the Ministry of Agriculture under the license numbers BA / 73 / 0936-8 / 2022 and BA / 73 / 00023-7 / 2023. All possible measures were taken to minimize pain and discomfort of the animals in accordance with the Directive 40 / 2013. (II.14.): ‘On animal experiments’ issued by the Government of Hungary, and the Directive 2010 / 63 / EU ‘On the protection of animals used for scientific purposes’ issued by the European Parliament and the European Council. Animals were housed in a large two-storey primate vivarium with closely observing their recommended daily metabolizable energy intake requirement and their species-specific social needs. Animals were fed once per day, in the afternoons, following the daily training and testing sessions. Diet was standard nutritionally complete lab chow especially designed for non-human primates (NHP pellets, Ssnifff Spezialdiäten GmbH, Germany) and was supplemented with fresh fruits and vegetables daily. Water was available ad libitum. In the home cages and testing rooms, temperature and relative humidity were maintained at 24 ± 2 ◦C and 55 ± 5%, respectively. Six (4 male) 3-year-old cynomolgus monkeys were included in the study, weighing 3.32 ± 0.51 kg at the beginning of the experiments. The animals were transported between their place of residence (GTRC, Kővágószőlős) and the neuroimaging site (Medicopus Ltd., Kaposvár) in a specially designed air- conditioned, and camera-equipped van (Dacia Dokker Van) in a special primate transport cage. The transport of the animals took approximately one hour each way. Before the experiments all animals were intensively conditioned and accustomed to the transport cage with positive reinforcement training (PRT). (The transport cage can be attached to the housing cage, and the animals regularly visited it and receive their daily food in the transport cage). Thus, the transport to and from the measurement site was done with minimal stress effects on the animals. Before anesthesia, animals were food and water deprived for 6 and 2 h respectively. The anesthetic protocol was adapted to the individual sensitivity of the animals. The main objective was to ensure a steady deep anesthesia during the experiments, with adequate oxygen saturation and normal body temperature. For premedication, animals were first lightly anesthetized with a single dose of intramuscular (i.m.) ketamine injection (0.25 mg / kg, CP Ketamin, CP-Pharma, HU) and received a single dose of atropine injection i.m. (0.04-0.05 mg / kg, Atropinum Sulphuricum, Egis, HU) to prevent salivation. Then, animals received a mixture of 3.5-5% v / v isoflurane (Aerrane, Baxter, US) gas in 2 L / min flow of pure O2 through a face mask to induce deep aesthesia using a ventilation system in Mapleson-D arrangement. After achieving the adequate depth of anesthesia, an orally introduced supraglottic airway tube (laryngeal mask, Fazzini, IT) was inserted around the laryngeal inlet of the trachea and was sealed via a low-pressure cuff to secure the airway and stabilize ventilation. To maintain a stable level of deep anesthesia throughout the experiments, a mixture of 1.5 V / V% isoflurane in 2 L / min pure O2 flow was used. After the experiments, the laryngeal mask was removed, and animals were allowed to inhale pure O2through a face mask until becoming awake. Then, they were returned to the transport cage and were continuously monitored and were offered with high sugar-containing fruits (banana) and water. When animals spontaneously accepted food and showed normal behavior without signs of sedation they were ready to be returned to their place of residence. The total recovery (wake-up) time varied between 1 and 1.5 hours to reach a transportable state. In vivo PET imaging of Example 8 The cynomolgus monkey (3.2 kg, female) received a single i.v. injection of Example 8 (140 MBq / 3 mL). The PET measurement protocol was optimized explicitly for cynomolgus monkey. During measurement both MRI (Siemens Biograph mMR MR-PET camera) and CT (SIEMENS Biograph TruePoint 64) scans are conducted simultaneously: firstly 60 min PET / MRI scan followed by a 25 min PET / CT scan (Figure 8A and 8B). A TAC of 8 brain regions were generated, using the level 1 VOI system in Cortical Hierarchy Atlas of the Rhesus Macaque (CHARM) atlas (frontal lobe, parietal lobe, temporal lobe, occipital lobe, telencephalon, diencephalon, mesencephalon, metencephalon). A short accumulation period (3-4 minutes) was detected (n = 4 monkeys), followed by a 10 min saturation and 45 min slow decreasing period (Figure 9A and Figure 9B, respectively).

Claims

CLAIMS 1. A compound of general formula (I)wherein A is CH or N; R1is18F and R2is a CH3, or a CH(CH3)2 group, or R1is F and R2is a11CH3 group; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, selected from the group consisting of: 4-{[4-(18F)fluorophenyl]methoxy}-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl]pyridin-2(1H)-one, 4-{[4-(18F)fluorophenyl]methoxy}-1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl)pyridin-2(1H)-one, 4-[(4-Fluorophenyl)methoxy]-1-[3-(11C)methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl]pyridin-2(1H)-one, 4-[(5-Fluoropyridin-2-yl) methoxy]-1-[3-(11C)methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl]pyridin-2(1H)-one, and a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, selected from the group consisting of: 4-{[4-(18F)fluorophenyl]methoxy}-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl]pyridin-2(1H)-one,4-{[4-(18F)fluorophenyl]methoxy}-1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl)pyridin-2(1H)-one, 4-[(4-Fluorophenyl)methoxy]-1-[3-(11C)methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl]pyridin-2(1H)-one, and a pharmaceutically acceptable salt thereof.

4. A compound of general formula (II):wherein R1is a B(O-C(R3)2-C(R3)2-O) group, R2is a CH3, a CH(CH3)2, or a COOC(CH3)3group, R3is a CH3, or a C2H5group, or a salt thereof.

5. The compound according to claim 4, selected from the group consisting of: 1-[3-(Propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl]-4-{[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyridin-2(1H)-one, 1-(3-Methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)-4-{[4-(4,4,5,5- tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyridin-2(1H)-one, 4-{[4-(4,4,5,5-Tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}-1-(2,3,4,5-tetrahydro- 1H-[1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one hydrochloride salt, and tert-Butyl 9-[2-oxo-4-{[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyri- din-1(2H)-yl]-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate.

6. A compound of general formula (III):wherein A is CH or N or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6, selected from the group consisting of 4-[(4-fluorophenyl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9- yl)pyridin-2(1H)-one maleate salt, and 4-[(5-fluoropyridin-2-yl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9- yl)pyridin-2(1H)-one maleate salt.

8. A compound according to any one of claim 1 to 3, for use as PET tracers.

9. A compound according to any one of claim 1 to 3, for use in visualizing localization or distribution of MCHR1 receptors in mammals by means of PET imaging.

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