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

Abstract

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.

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

“…The non-radioactive reference compound MCH was purchased from Sigma-Aldrich ® (Sigma-Aldrich, St. Louis, MO, USA). The MCHR1 antagonists including the racemic mixture of SNAP-7941 ((±)-SNAP-7941), the enantiomeric form (+)-SNAP-7941 and the fluoroethylated analogue (+)-(2-Fluoroethyl)(4 S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amin]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetra-hydro-5-pyrimidenecarboxylate (FE@SNAP), as well as the precursor compounds (4S)-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 acid (SNAP-acid) and 2-(Tosyloxy)ethyl-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 acid (Tos@SNAP) were synthesized in collaboration with the Department of Pharmaceutical Chemistry and the Department Organic Chemistry of the University of Vienna (Vienna, Austria) as previously reported 36 , 37 . All other chemicals were of analytical grade and purchased from commercial sources.…”

Discovery of melanin‐concentrating hormone receptor 1 in brown adipose tissue

“…All PET‐tracers were physiologically formulated and fulfilled the quality control parameters. The corresponding unlabeled compound SNAP‐7941 ((±)‐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)) and the precursor SNAP‐acid ((±)−3‐{[(3‐{4‐[3‐(acetylamino)phenyl]−1‐piperidinyl}propyl)amino]carbonyl}−4‐(3,4‐difluorophenyl)−6‐(methoxymethyl)−2‐oxo‐1,2,3,4‐tetra‐hydro‐5‐pyrimidenecarboxylate acid)) were synthesized according to Schirmer et al 47 . at the Departments of Pharmaceutical Chemistry and Organic Chemistry (University of Vienna, Austria).…”

“…) were synthesized according to Schirmer et al 47 at the Departments of Pharmaceutical Chemistry and Organic Chemistry (University of Vienna, Austria). The ADRB3 agonist CL316,243 (#1499) was purchased from Tocris Bioscience.…”

SNAPshots of the MCHR1: a Comparison Between the PET-Tracers [18F]FE@SNAP and [11C]SNAP-7941

“…The racemic mixture of SNAP-7941 ((±)-SNAP-7941), the fluoroethylated analog (±)-(2-fluoroethyl)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amin]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetra-hydro-5-pyrimidenecarboxylate (FE@SNAP), as well as the precursor compounds (±)-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 acid (SNAP-acid), and (±)-2-(tosyloxy)ethyl-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 acid (Tos@SNAP) were provided by the Department of Pharmaceutical Chemistry and the Department Organic Chemistry of the University of Vienna (Vienna, Austria) [ 33 ]. Tariquidar methanesulfonate (TQD) was purchased from MedChem Express (Princeton, NJ, USA).…”

“…The radiosynthesis of [ 11 C]SNAP-7941, the radiolabeled analog of (±)-SNAP-7941, was performed in a fully automated synthesizer (TRACERlab™ FX C Pro, GE Healthcare, Germany) as previously reported [ 30 , 33 ]. Radiosynthesis of [ 18 F]FE@SNAP was performed in a microfluidic device (Advion NanoTek®, Ithaca, NY, USA) as described elsewhere [ 37 ], followed by purification in a conventional synthesizer unit (Nuclear Interface®, GE Medical Systems, Uppsala, Sweden) [ 36 , 38 ].…”