Structure-Based Design, Optimization, and Development of [¹⁸F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

Abstract

The cannabinoid receptor type 2 (CB2R) is an attractive target for the diagnosis and therapy of neurodegenerative diseases and cancer. In this study, we aimed at the development of a novel 18F-labeled radioligand starting from the structure of the known naphthyrid-2-one CB2R ligands. Compound 28 (LU13) was identified with the highest binding affinity and selectivity versus CB1R (CB2RK i = 0.6 nM; CB1RK i/CB2RK i > 1000) and was selected for radiolabeling with fluorine-18 and biological characterization. The new radioligand [ 18 F]­LU13 showed high CB2R affinity in vitro as well as high metabolic stability in vivo. PET imaging with [ 18 F]­LU13 in a rat model of vector-based/-related hCB2R overexpression in the striatum revealed a high signal-to-background ratio. Thus, [ 18 F]­LU13 is a novel and highly promising PET radioligand for the imaging of upregulated CB2R expression under pathological conditions in the brain.

Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

“…Several CB 2 R ligands have been developed and evaluated (Ni et al, 2019b), including [ 11 C]NE40 (Vandeputte et al, 2012), [ 11 C]A-836339 (MDTC) (Pottier et al, 2017;Du et al, 2022), [ 18 F]MA3 (Attili et al, 2019), [ 18 F]FC0324 (Caillé et al, 2017), [ 18 F]JHU94620 (Moldovan et al, 2016), [ 18 F]LU13 (Gündel et al, 2022), [ 18 F]DM102 (Modemann et al, 2022), [ 18 F]CRA13 (Hassan et al, 2020), [ 11 C]RS-016 (Meletta et al, 2017), [ 11 C]RS-028 (Haider et al, 2018), [ 11 C]RSR-056 (Slavik et al, 2015), and [ 18 F]RoSMA-18-d6 (Haider et al, 2020). Thus far, only one in-human in vivo CB 2 R PET using [ 11 C]NE40 (Ahmad et al, 2016) in patients with AD and healthy controls has been reported, showing no group difference.…”

Evaluation of CB2R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

“…CB 2 R has been shown to be increased and involved in Aβ pathology in 5×FAD [61,31] and J20 mouse models of AD amyloidosis [24] but reduced in the brains of 3×Tg mice (with both amyloid and tau pathology) and aging C57B6 mice [56]. Several CB 2 R ligands have been developed and evaluated [39], including [ 11 C]NE40 [54], [ 11 C]A-836339 (MDTC) [9,42], [ 18 F]MA3 [4], [ 18 F]FC0324 [6], [ 18 F]JHU94620 [35], [ 18 F]LU13 [14], [ 18 F]DM102 [34], [ 18 F]CRA13 [17], [ 11 C]RS-016 [32], [ 11 C]RS-028 [16], [ 11 C]RSR-056 [50] and [ 18 F]RoSMA-18-d6 [15]. Thus far, only one in-human in vivo CB 2 R PET using [ 11 C]NE40 [1] in patients with AD and healthy controls has been reported, showing no group difference.…”

Diagnostic and Therapeutic Radiopharmaceuticals

“…Novel chelators have been reported to be able to incorporate, with high yields, radiometals such as [ 203 Pb]­Pb 2+ , [ 213 Bi]­Bi 3+ , [ 225 Ac]­Ac 3+ , and [ 90 Y]­Y 3+ in short reaction times and under mild conditions with a broad range of pH values. − Metal–ligand complexes have been confirmed by 1 H NMR spectroscopy, X-ray crystallography, potentiometry, and computational studies. − Development of novel radiotracers to image central nervous system (CNS) receptors. Radiopharmaceuticals binding opioid σ2 receptors, purinergic P2Y 12 receptors, sphingosine-1-phosphate receptor 1, α7 nicotinic acetylcholine receptors, cannabinoid receptor type 2, and Aβ oligomers and plaques have been studied in rodents and non-human primates, demonstrating their ability to cross the blood–brain barrier and bind to CNS targets. Ligand–target interactions at the atomic level have been predicted by perturbation free-energy calculations, molecular docking, molecular dynamics, and metadynamics simulations. ,, Development of radioligands for cancer imaging and therapy with prolonged half-life in vivo and high tumor-to-background contrast.…”

“…Development of novel radiochemical reactions or chelators to incorporate diagnostic and therapeutic radionuclides in their chemical structure. 10−14 Papers describing novel methods for radiocyanation of aryl halides for the introduction of [ 11 C]CN into peptides, 15 18 F-trifluoromethylation of unmodified peptides at tryptophan and tyrosine residues, 16 and formation of [ 22 sphingosine-1-phosphate receptor 1, 23 α7 nicotinic acetylcholine receptors, 24 cannabinoid receptor type 2, 25 and Aβ oligomers 26 and plaques 27 have been studied in rodents and non-human primates, demonstrating their ability to cross the blood−brain barrier and bind to CNS targets. Ligand−target interactions at the atomic level have been predicted by perturbation free-energy calculations, molecular docking, molecular dynamics, and metadynamics simulations.…”

“…Development of novel radiotracers to image central nervous system (CNS) receptors. Radiopharmaceuticals binding opioid σ2 receptors, purinergic P2Y 12 receptors, sphingosine-1-phosphate receptor 1, α7 nicotinic acetylcholine receptors, cannabinoid receptor type 2, and Aβ oligomers and plaques have been studied in rodents and non-human primates, demonstrating their ability to cross the blood–brain barrier and bind to CNS targets. Ligand–target interactions at the atomic level have been predicted by perturbation free-energy calculations, molecular docking, molecular dynamics, and metadynamics simulations. ,, …”