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. 2025 Dec;45(12):2417-2427.
doi: 10.1177/0271678X251371377. Epub 2025 Sep 18.

Evaluation of deuterated [18F]JHU94620 for imaging cannabinoid type 2 receptors in rodent and monkey brain

Mudasir Maqbool  1 , Daniel Gündel  2 , Jeih-San Liow  1 , Jinsoo Hong  1 , Paul A Parcon  1 , Raven Cureton  1 , Matilah T Pamie-George  1 , Adrian E Jenson  1 , Shawn Wu  1 , Ioline D Henter  1 , Sami S Zogbhi  1 , Victor W Pike  1 , Rareş-Petru Moldovan  2 , Robert B Innis  1
Affiliations

Evaluation of deuterated [18F]JHU94620 for imaging cannabinoid type 2 receptors in rodent and monkey brain

Mudasir Maqbool et al. J Cereb Blood Flow Metab. 2025 Dec.

Abstract

PET imaging of cannabinoid type-2 receptors (CB2Rs) in the healthy brain remains challenging due to low receptor density and the unavailability of radiotracers with high affinity and selectivity. Because some carbon-deuterium bonds are less susceptible than carbon-proton bonds to enzymatic cleavage, deuteration of [18F]JHU94620 was pursued to potentially slow its metabolism. This study: (1) evaluated the sensitivity of a heavily deuterated version of the agonist [18F]JHU94620 ([18F]JHU94620-d8) to detect brain CB2Rs in healthy Sprague-Dawley rats and monkeys and in a rat model of inflammation; (2) assessed the metabolic stability of [18F]JHU94620 and [18F]JHU94620-d8 in whole blood, plasma, and brain of control (FVB) mice and in the whole blood and plasma of monkeys; and (3) investigated the efflux transporter substrate liability of [18F]JHU94620-d8. Deuteration of [18F]JHU94620 did not significantly affect its uptake in the brains of FVB mice, Sprague-Dawley rats, or monkeys, nor did it affect metabolic stability, except in FVB mice. [18F]JHU94620-d8 was also found to be a moderate substrate for efflux transporters in monkeys but not in mice. The sensitivity of [18F]JHU94620-d8 was inadequate to detect the low density of CB2Rs that are in the agonist-preferring state in the brain.

Keywords: CB2 receptor; PET imaging; PET tracer; brain uptake; metabolic stability.

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Conflict of interest statement

Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

The image presents various graphs and images depicting results from experiments with [18F]JHU94620 and its deprotonated form (d8) on mice and rats. Graphs illustrate the radioactivity uptake in brain and jawbone over time, with separate lines for mandible and brain uptakes in both species. Two molecular structures of the respective compounds are also shown, alongside mean PET images displaying radioactivity distribution in the brain and jawbone of mice and rats.
Figure 1.
(a) Chemical structure of [18F]JHU94620 and [18F]JHU94620-d8. Radioactivity uptake of [18F]JHU94620 (n = 2) in brain and jawbone of mice (b, n = 2) and rats (d, n = 2). Radioactivity uptake of [18F]JHU94620-d8 in brain and jawbone of mice (c, n = 3) and rats (e, n = 2). (f) Mean PET images showing radioactivity uptake with [18F]JHU94620 and [18F]JHU94620-d8 in brain and jawbone of mice and rats (0–120 min). M: mouse; PET: positron emission tomography; R: rat.
The image presents three radiochromatography graphs comparing the radioactivity clearance rates of [18F]JHU94620 in both brain tissue and plasma after intravenous administration, with an HPLC reference chromatogram.
Figure 2.
Comparative ex vivo radiochromatographic analysis of radioactivity in mouse brain tissue (a) and plasma (b) 30 min post-intravenous administration of [18F]JHU94620. (c) An HPLC reference chromatogram of [18F]fluoride.
Comparison of [18F]JHU94620 with [18F]JHU94620-d8 in monkey brain radioactivity uptake, plasma parent concentration, and composition. Graphs in (a) (b) (c) Stable normal distribution volume time. Peaks in (e) (f) Graphs 30 minutes after tracer injection in monkeys. SUV: standardized uptake value.
Figure 3.
Deuteration of [18F]JHU94620 did not alter brain radioactivity uptake, plasma parent concentration, or plasma parent composition in monkeys. (a) Whole brain radioactivity uptake with [18F]JHU94620-d8 and [18F]JHU94620 in monkeys (n = 1 monkey for each condition). (b) Plasma parent concentration (SUV) of [18F]JHU94620-d8 and [18F]JHU94620. (c) Varying percentages of [18F]JHU94620-d8 and [18F]JHU94620 and their respective radiometabolites in plasma over time. (d) Normalized distribution volume (VT) time stability curves to the endpoint of the [18F]JHU94620-d8 and [18F]JHU94620 scans. (e, f) Plasma radiochromatograms of [18F]JHU94620-d8 and [18F]JHU94620 30 min after tracer injection in monkeys. SUV: standardized uptake value.
This image presents data from a study on a monkey, showing radioactivity uptake in the whole brain and specific regions under baseline and blocked conditions with [18F]JHU94620-d8. Whole brain uptake, plasma parent concentration, and total distribution volume in regions like pons, caudate, putamen, hippocampus, cerebellum, and cortex are depicted. MRI and PET images are included to visualize brain tissue and radiotracer distribution.
Figure 4.
[18F]JHU94620-d8 showed no blocking effect by non-radioactive JHU94620 in monkey (n = 1). (a) Whole brain radioactivity uptake in monkeys, where quick brain uptake and fast washout were observed under both baseline and blocked conditions (JHU94620, 1.5 mg/kg). (b) Plasma parent concentration of [18F]JHU94620-d8 remained unaltered under both baseline and blocked conditions. (c) Comparison of total distribution volume (VT; mL/cm3) of different regions of interest in monkey brain under baseline and blocked conditions. (d) T1-weighted MRI and PET images of monkey brain under baseline and blocked conditions. MRI: magnetic resonance imaging; PET: positron emission tomography.
The image presents data from a study involving Sprague-Dawley rats, focusing on the effects of LPS injection on CB2R protein expression and radioactivity uptake in rat brains over three days. The study compares whole brain radioactivity uptake, radioactivity on the injected side versus the un-injected side, and CB2R protein expression in LPS injected rat brain compared to control brain and spleen observed using simple western blotting.
Figure 5.
Sprague–Dawley rats (n = 6) were injected with 50 µg in 5 µL of LPS unilaterally into their right striatum and underwent PET scanning on days 1, 9, and 15 using [18F]JHU94620-d8 as the tracer. JHU94620 (1.5 mg/kg) was used as a blocking agent (n = 3). (a) Whole brain radioactivity uptake in rats on day 9 post-LPS injection and after CB2R blockade with JHU94620. (b) Radioactivity uptake on day 9 post-LPS injection on the LPS=injected side versus un-injected side. (c) CB2R protein expression in LPS injected rat brain compared to control brain and spleen observed using simple western blotting. (d) Mean PET images (0–120 min) of LPS-treated rat brains on days 1, 9, and 15. Red arrows indicate the site of the LPS injection. LPS: lipopolysaccharide; PET: positron emission tomography.
Whole brain uptake in Monkey and brain regions in Figure 1 : Baseline versus elacridar-treated whole brain and specific brain regions with [18F]JHU94620-d8, showing reduced activity and changes in plasma concentration, with an increase in distribution volume of striatal region.
Figure 6.
[18F]JHU94620-d8 is a moderate substrate for efflux transporters in monkey. (a) Whole brain uptake in healthy monkey (n = 1) under baseline and pre-blocked conditions of efflux transporters with elacridar (3 mg/kg of body weight). (b) Time–concentration of [18F]JHU94620-d8 in plasma under baseline and efflux transporter blocked conditions in monkey (n = 1). (c) Comparison of total distribution volume (VT; mL/cm3) of different monkey brain regions (n = 1) under baseline and efflux transporter blocked conditions.
See this image and copyright information in PMC

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