Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

Abstract

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

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

“…Based on these initial findings, we conclude that [ 18 F]LU13 crosses the blood− brain barrier (BBB) and most likely binds specifically to the hCB2R. In comparison to [ 18 F]5, another CB2R-targeted radioligand recently reported by us, 46 the high and stable concentration of activity in the target region between 20 and 60 min p.i. makes [ 18 F]LU13 more suitable for static PET imaging.…”

“…a SUVr of 7.8 ± 1.6 for the target region-to-control and of 8.8 ± 4.3 for the target region-to-cerebellum were obtained, which are slightly higher compared to those of [ 18 F]5 46 . In both reference regions, the activity concentration over time area under the curve (AUC) of [ 18 F]LU13 was 3.8 times lower compared to that of the target region (Table 2) and confirmed the use of the contralateral region and cerebellum as eligible reference regions in the animal model, as already shown by the use of [ 18 F]5 46 (Table 2).…”

“…Moreover, these compounds possess a relatively high molecular weight (MW > 450) and higher lipophilicity with cLogP in the range of 4.5−5 compared to [ 18 F]5, which has a cLogP of 3.5 and an experimentally determined logD 7.4 of 3.15. 46 Keeping in mind the favorable range of logD for braintargeting pharmaceuticals (logD, 1−4), 54,55 we redirected our attention for the C-6 non-substituted derivatives and extended the series of derivatives mainly by modifying the substituent at the carboxamide subunit. The introduction of an aryl moiety at this position had a strong impact on the binding affinity of the resulting compounds, and each of the (fluoro)phenyl and (fluoro)pyridyl derivatives 22−27 showed CB2RK i s in the micromolar range.…”

“…Recently, we reported the development and preliminary evaluation of [ 18 F]LU14 ([ 18 F]5, Figure 2) and provided evidence for the brain-penetrant nature of this scaffold. 46 Compound [ 18 F]LU14 was developed based on a library of naphthyridine-2-one-carboxamides developed by Lucchesi and co-workers and further investigated by Pascali and co-workers. 47,48 Thus, in the present work, we report our efforts to develop a novel 18 F-labeled radioligand with improved binding affinity and metabolic stability by systematically modifying the structure of the literature-known naphthyrid-2one based CB2R ligands (compounds 5, 10, and 16).…”

“…46,47,49 A schematic overview of our structure-based optimization program is shown in Figure 2, highlighting the three positions at which modifications are performed: (i) the carboxamide subunit, (ii) the N-alkyl chain, and (iii) the C-6 position. Previous work reported by Lucchessi 47 and by us 46 proved the superior binding affinity of the ligands bearing a cisconfiguration of the 4-methyl cyclohexylamine. Therefore, in the present work we focus on evaluating the novel compounds in the diastereomerically pure form.…”