PET Imaging Reveals CB1 Receptor Drugs Need Only 20-30% Brain Occupancy for Anti-Obesity Effects | Research

The takeaway

PET brain imaging in primates showed that the clinical doses of CB1 receptor blockers rimonabant and taranabant that produce weight loss only occupy about 20-30% of CB1 receptors, much less than expected for this class of drugs.

Read this if you follow cannabinoid receptor drug development or the science behind anti-obesity medications.

Only 20-30% CB1 receptor occupancy needed for clinical weight loss effects

What the researchers found

As part of efforts to develop safer anti-obesity drugs targeting the CB1 receptor, researchers used PET brain imaging in six non-human primates to measure how much of the CB1 receptor population different drugs actually occupied at therapeutic-equivalent doses.

The surprise finding was that rimonabant and taranabant, both proven effective for weight loss in humans, only needed to occupy about 20-30% of CB1 receptors to produce their therapeutic effects. This is much lower than the typical 60-80% occupancy needed for most drugs targeting G-protein coupled receptors.

Three novel CB1 antagonists developed by AstraZeneca showed similar binding characteristics. The researchers also noted that "neutral" CB1 antagonists (which block the receptor without reducing its baseline activity) might achieve therapeutic benefit with fewer psychiatric side effects than inverse agonists like rimonabant.

Why it matters

Understanding that only 20-30% receptor occupancy is needed for therapeutic effects opens the possibility of using much lower doses of CB1 antagonists, potentially staying below the threshold for psychiatric side effects while maintaining efficacy. This finding could guide clinical dose optimization for future CB1-targeting drugs.

The numbers in context

42 PET measurements in 6 primates. 5 CB1 antagonists tested. Clinical efficacy doses produced only 20-30% CB1 receptor occupancy. Typical GPCR antagonists require 60-80% occupancy. Three novel AstraZeneca compounds showed binding affinity similar to rimonabant and taranabant.

How the study worked

Forty-two PET measurements in six non-human primates using the CB1-specific radioligand [11C]SD5024. Five CB1 receptor antagonists were compared for receptor occupancy relative to dose and plasma exposure. Occupancy at clinically effective doses was estimated.

What this study cannot tell us

Non-human primate pharmacokinetics may differ from humans. The 20-30% occupancy estimate is an approximation based on cross-species dose translation. No direct measurement of psychiatric side effects at different occupancy levels was performed.

How to read the evidence

Carefully controlled PET imaging study in primates with multiple compounds, but occupancy-efficacy and occupancy-side effect relationships require human confirmation.

When this study was published

Published in 2016. Development of peripherally restricted and neutral CB1 antagonists has continued.

The bigger picture

The failure of rimonabant and taranabant due to psychiatric side effects stalled the field of CB1-based obesity treatment. This PET data suggests that the problem may have been dose-related rather than target-related, reinvigorating interest in developing CB1 antagonists at more carefully optimized doses.

Questions still open

Is there a receptor occupancy threshold below which psychiatric side effects do not occur? Would neutral CB1 antagonists at 20-30% occupancy produce weight loss without depression or anxiety?

Common questions

Why were CB1 receptor blockers pulled from the market?

Rimonabant and taranabant caused depression and anxiety at the doses used for weight loss. This PET study suggests those doses may have been higher than necessary for the therapeutic effect.

Could lower doses work without side effects?

The finding that only 20-30% receptor occupancy is needed for efficacy suggests that lower doses might maintain weight loss benefits while staying below the threshold for psychiatric side effects, though this needs human testing.

Read the original research

A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.

Neuropharmacology, 101, 519-30

View on PubMed ↗Publisher’s paper ↗

Citation

Hjorth, Stephan; Karlsson, Cecilia; Jucaite, Aurelija; Varnäs, Katarina; Wählby Hamrén, Ulrika; Johnström, Peter; Gulyás, Balázs; Donohue, Sean R; Pike, Victor W; Halldin, Christer; Farde, Lars. (2016). A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.. Neuropharmacology, 101, 519-30. https://doi.org/10.1016/j.neuropharm.2015.03.002