Medicinal Chemistry & Chemical Biology, Contributed Talk (15min)

PET Imaging of Cannabinoid Type 2 Receptors – Discovery of [18F]RoSMA-18-d6

L. Gobbi1
1F. Hoffmann-La Roche -

Luca Gobbi1, Ahmed Haider2, Julian Kretz1, Christoph Ullmer1, Andreas Brink1, Michael Honer1, Dieter Muri1, Adrienne Müller Herde2, Francesco Spinelli2, Hazem Ahmed2, Kenneth Atz1, Claudia Keller2, Roger Schibli2,3, Linjing Mu2,3, Uwe Grether1, Simon M. Ametamey2

1Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, 4070 Basel, Switzerland;  2Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland;  3Department of Nuclear Medicine, University Hospital Zurich, 8091 Zurich, Switzerland

The cannabinoid type 2 receptor (CB2) is a member of the GPCR cell surface receptors. CB2 has been recognized to be broadly involved in neuroinflammatory processes, but no suitable CB2-targeted probe is currently available for clinical use. In a collaborative medicinal chemistry program based on a partnership between academia and pharma industry, we have identified the pyridine-based CB2 PET radioligand [18F]1 with a binding affinity (Ki) of 6 nM for CB2 and a selectivity factor of 696 over the cannabinoid receptor type 1 (CB1) [1]. Despite the promising in vitro properties, [18F]1 exhibited only moderate in vivo specificity and a fast washout from rat spleen, an organ rich in CB2. In an effort to improve CB2 specificity and selectivity we synthesized 15 derivatives of [18F]1 and tested them for their binding affinities towards CB2 and CB1. As a result from this work, RoSMA-18 was identified as a novel tracer candidate displaying an affinity of 0.7 nM (Ki for CB2) and an exquisite selectivity factor of > 12’000 over CB1 [2]. [18F]RoSMA-18 was synthesized with an average radiochemical yield of 10.6 ± 3.8% (n = 16) and excellent radiochemical purity (> 99%). Molar activities ranged from 52 - 65 GBq/µmol. Exceptional CB2 specificities were achieved in CB2-positive rat spleen by in vitro autoradiography (71 ± 2%) and ex vivo biodistribution (86 ± 2%), which are superior to any previously reported CB2 PET radioligand. The very high specificity was further demonstrated in CB2 knockout mouse spleen. PET experiments revealed specific and reversible CB2 binding of [18F]RoSMA-18 in the CB2-positive rat spleen. Metabolite studies detected only intact [18F]RoSMA-18 in the rat brain, however, in vivo defluorination was observed as evidenced by skull uptake. The defluorination was effectively prevented by replacing the hydrogen atoms in the fluoropropyl side chain with deuterium atoms to afford [18F]RoSMA-18-d6. RoSMA-18-d6 showed a Ki value of 0.8 nM for CB2 and > 10 µM for CB1. Overall, these results suggest that [18F]RoSMA-18-d6 is a promising CB2 PET radioligand for clinical translation.

[1]   A. Haider et al., J. Med. Chem, 2019, 62, 11165-11181.
[2]   A. Haider et al., J. Med. Chem, 2020, 63, 10287-10306.