Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors.
Ahmed HaiderLuca C GobbiJulian KretzChristoph UllmerAndreas BrinkMichael HonerThomas J WolteringDieter MuriHans IdingMarkus BürklerMartin BinderChristian BartelmusIrene KnueselPal PacherAdrienne Müller HerdeFrancesco SpinelliHazem AhmedKenneth AtzClaudia KellerMarkus WeberRoger SchibliLinjing MuUwe GretherSimon M AmetameyPublished in: Journal of medicinal chemistry (2020)
Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity (Ki for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d6 exhibited outstanding in vitro performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% (n = 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [18F]RoSMA-18-d6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [18F]RoSMA-18-d6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [18F]RoSMA-18-d6 is a promising CB2 PET radioligand for clinical translation.
Keyphrases
- positron emission tomography
- computed tomography
- pet imaging
- pet ct
- spinal cord
- high resolution
- endothelial cells
- cell proliferation
- radiation therapy
- gene expression
- squamous cell carcinoma
- signaling pathway
- cancer therapy
- mass spectrometry
- cell therapy
- living cells
- rectal cancer
- bone marrow
- transcription factor
- locally advanced
- fluorescent probe