Entwicklung neuartiger Imidazol und Indan-Indol basierter PET Radioliganden für die Bildgebung von Cannabinoid CB2 Rezeptoren

• Antragsteller: Dr. Rares-Petru Moldovan
• Fachliche Zuordnung: Pharmazie ; Nuklearmedizin, Strahlentherapie, Strahlenbiologie ; Organische Molekülchemie - Synthese, Charakterisierung
• Förderung: Förderung von 2018 bis 2022
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 405969525

• Erstellungsjahr: 2024

Zusammenfassung der Projektergebnisse

This research project proposed the medicinal chemistry, radiochemistry and biological evaluation of two classes of CB2R ligands namely imidazole and indole respectively. For the indole class of compounds an enantioselective synthesis was developed and a small library of fluorinated derivatives was synthesized in enantiomeric pure form. From this class, compound RM365 showed the best CB2R affinity and was radiosynthesized in presence of copper catalyst starting from the corresponding boronic acid pinacol ester precursor. Its biological evaluation revealed that [18F]RM365 i) has high affinity towards hCB2R but no or low affinity towards rCB2R, ii) is high metabolic stabile with ~90% intact radioligand detected in the brain at 30 min p.i. iii) is able to label CB2R in the brain of a rat model of local hCB2R overexpression in reversible manner. These results support further evaluation of [18F]RM365 towards clinical use but not in preclinical animal models due to species related binding affinity differences. The evaluation of imidazole class of compounds, led to the development of [18F]RM259 which proved to be unsuitable for imaging of the CB2R in the brain due to high nonspecific binding as observed by in vitro autoradiography performed with rodent brain tissue. For this reason, two additional classes of compounds were evaluated for the possibility to develop a novel radioligand for CB2R imaging with PET namely naphthyrid-2-one and thiazole. For both classes of compounds a systematic medicinal chemistry program was performed, leading to the development of novel fluorinated compounds with high affinity towards CB2R and suitable for radiolabelling. Out of this medicinal chemistry program, four new radioligands were developed namely i) [18F]LU13 and [18F]LU14 for the naphthyrid-2-one class and ii) [18F]LUZ5 and [18F]JHU94620-d8 for the thiazole class of compounds. All new radioligands underwent a step by step biological evaluation, starting with in vitro autoradiography and KD determination, followed by metabolism and PET study in healthy rodents and finally, the evaluation of the most promising candidates in our rat model of local CB2R overexpression. Within this funding period, our study identified [18F]JHU94620-d8 as the most suitable radioligand for the imaging of the CB2R in the brain with PET.

Projektbezogene Publikationen (Auswahl)

• Development of selective CB2 receptor inhibitors as potential probes for molecular imaging with positron emission tomography, 7th Conference On Molecular Mechanisms of Regulation in the Nervous System, Milano, 2019
  Peter Brust & Rareş-Petru Moldovan
  
• Copper-mediated automated radiofluorination and biological evaluation of a highly affine cannabinoid receptor type 2 ligand with PET, Journal of Nuclear Medicine 2020, 61 (supplement 1) 197
  Rodrigo Teodoro, Magali Toussaint, Daniel Gundel, Winnie Deuther-Conrad, Barbara Wenzel, Peter Brust & Rares-Petru Moldovan
  
• [18F]JHU94620-d8 – A new radiotracer for the assessment of the CB2 receptor expression in brain and peripheral tissues by PET, 16th Annual Meeting of the European Society of Molecular Imaging, 2021
  Daniel Gündel, Winnie Deuther-Conrad, Magali Toussaint, Rodrigo Teodoro, Guy Bormans, Peter Brust & Rareş-Petru Moldovan
  
• Development and preliminary evaluation of [18F]JHU94620- d8 for PET imaging of cannabinoid receptors type 2. Annual DPhG - Meeting 2021, Invited speaker
  Rareş-Petru Moldovan
  
• Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain. International Journal of Molecular Sciences, 22(15), 8051.
  Teodoro, Rodrigo; Gündel, Daniel; Deuther-Conrad, Winnie; Ueberham, Lea; Toussaint, Magali; Bormans, Guy; Brust, Peter & Moldovan, Rareş-Petru
  
• Development of fluorinated and methoxylated benzothiazole derivatives as highly potent and selective cannabinoid CB2 receptor ligands. Bioorganic Chemistry, 114, 105191.
  Aly, Mayar W.; Ludwig, Friedrich-Alexander; Deuther-Conrad, Winnie; Brust, Peter; Abadi, Ashraf H.; Moldovan, Rareş-Petru & Osman, Noha A.
  
• Imaging of the human CB2 receptors in the brain with PET: Development and biological evaluation of [18F]JHU94620-d8. Nuklearmedizin - NuclearMedicine, 60. Georg Thieme Verlag KG.
  Gündel, D.; Teodoro, R.; Deuther-Conrad, W.; Toussaint, M.; Borman, G.; Brust, P. & Moldovan, RP
  
• Synthesis of carborane-based ligands for theranostic approaches, The 9th European Conference on Boron chemistry, 2022
  Lea Ueberham, Rareş-Petru Moldovan, Martin Kellert, Winnie Deuther-Conrad, Daniel Gündel, Peter Brust & Evamarie Hey-Hawkins