Development of a Novel Carbon-11 Labeled PET Radioligand for Melanin- Concentrating Hormone Receptor 1

Curr Radiopharm. 2017;10(1):35-40. doi: 10.2174/1874471009666161230113630.

Abstract

Background and objective: Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents and many drug discovery programs have been dedicated to identify smallmolecule antagonists of melanin-concentrating hormone receptor 1 (MCHR1). The aim of this study was to develop a positron emission tomography (PET) tracer for MCHR1 for translation of preclinical pharmacology to clinic to enhance success rate of drug discovery programs.

Methods: We identified 4-(cyclopropylmethoxy)-N-[8-methyl-3-({[(1-methyl-1H-pyrrol-2-yl)methyl] amino}ethyl)quinolin-7-yl]benzamide (Compound II) from Takeda MCHR1 antagonist library by utilizing binding affinity, log D value, physicochemical parameters ideal for a central nerve system agent, and synthetic feasibility of corresponding carbon-11 labeled radioligands as selection parameters for tracer candidates.

Results: In the rat PET study, [11C] Compound II showed clear uptake in the caudate/putamen with the pretreatment of cyclosporine A and its uptake was higher than that in the cerebellum where expression of MCHR1 was reported to be low.

Conclusion: In summary, [11C]Compound II is a promising lead compound for developing a suitable MCHR1 PET radioligand. [11C]Compound II, in combination with cyclosporine A, could be used as a research tool to visualize and quantify MCHR1 in rodents.

Keywords: Carbon-11; MCHR1; PET radioligand; brain imaging; cyclosporine A; positron emission tomography (PET).

MeSH terms

  • Animals
  • Anti-Obesity Agents / pharmacology
  • Benzamides / pharmacology*
  • Brain / metabolism*
  • Carbon Radioisotopes
  • Cyclosporine / pharmacology
  • Drug Design
  • Drug Discovery
  • Hypothalamic Hormones / antagonists & inhibitors*
  • Ligands
  • Melanins / antagonists & inhibitors*
  • Molecular Structure
  • Pituitary Hormones / antagonists & inhibitors*
  • Positron-Emission Tomography*
  • Quinolines / pharmacology*
  • Rats
  • Receptors, Somatostatin

Substances

  • 4-(cyclopropylmethoxy)-N-(8-methyl-3-(1-(pyrrolidin-1-yl)ethyl)quinolin-7-yl)benzamide
  • Anti-Obesity Agents
  • Benzamides
  • Carbon Radioisotopes
  • Carbon-11
  • Hypothalamic Hormones
  • Ligands
  • MCHR1 protein, rat
  • Melanins
  • Pituitary Hormones
  • Quinolines
  • Receptors, Somatostatin
  • melanin-concentrating hormone
  • Cyclosporine