5-HT2A receptor PET, functional MRI and serotonin: happy together?

The first direct evidence of an intrinsic serotonin deficit in the brains of people with major depression comes from a study using a newly-developed, serotonin-sensitive and highly selective PET tracer, David Nutt (Imperial College, London, UK) told CINP 2021 Virtual. The deficit in serotonin release correlates with depression severity.

Serotonin release capacity in the frontal cortex of people with major depressive disorder (MDD) is significantly lower than in healthy controls, according to a study using a newly-developed PET tracer, the highly selective 5-HT2A receptor agonist [11C]Cimbi-36.  

Moreover, the amount of serotonin released correlated significantly with illness severity: the worse the depression, the lower the serotonin release, David Nutt told a symposium on imaging the brain.

Serotonin deficit shown in the living brain

The study he reported, conducted by David Erritzoe, involved 12 people with depression (mean Beck score of 27) free of medication, and 12 healthy controls. [11C]Cimbi-36 PET was undertaken before and three hours after an oral dose of d-amphetamine, used as the serotonin releaser.


Long wait for direct evidence

It was fifty years ago that a link between depression and depleted levels of serotonin was first suggested by post mortem studies and the clinical observations that monoamine oxidase inhibiting drugs used for other indications had antidepressant effects.1 

The hypothesis was supported when CSF studies found a connection between low levels of the serotonin metabolite 5HIAA and violent suicide, by PET studies of 5-HT1A and 5-HT2A receptors showing abnormalities, by evidence that SSRIs blunted responsivity to fearful faces, and by the discovery that genetic variants, particularly at the serotonin transporter site, were associated with depression.

Newly-developed agonist tracer held the key

But, said Professor Nutt, we have had to wait until now – with the development of a tracer that is an agonist and not an antagonist, and a non-toxic means of releasing serotonin -- for proof of the involvement of a serotonin deficit in the living brain.

Is there a simpler way?

PET is an expensive technique and the new tracer not widely available. Amygdala hyper-reactivity to fearful faces as measured by functional MRI has been suggested as a key biological feature of depression2 and is reduced by serotonergic antidepressants.

So Professor Nutt and colleagues wondered whether it might be a more practical proxy measure of central serotonin function than the new PET technique.

Amygdala MRI reactivity to facial emotion was studied in ten patients on the same day as the PET scans.


Let’s face it: no correlation found

But there was no relationship between response to fearful faces on fMRI and frontal cortex deficit in serotonin release on PET. So this amygdala response seems not to be a helpful proxy for serotonin – although Professor Nutt did say that their finding should be regarded as preliminary until replicated with a larger numbers of subjects. 

New tracer links psilocybin to 5-HT2A receptor

The highly selective 5-HT2A receptor agonist [11C]Cimbi-36 PET radioligand was developed in collaboration with brain imaging colleagues in Copenhagen.3 It has also been used, for example, to show that the psychedelic effects of psilocybin correlate with 5-HT2A receptor occupancy.4

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.


1. Jacobsen JPR et al. Philos Trans R Soc Lond B Biol Sci. 2012; 367(1601): 2444–2459

2. Harmer CJ et al. Lancet Psychiatry 2017; 4(5):409-418

3. Ettrup A et al. Neuroimage 2016;130:167-174

4. Madsen MK et al. Neuropsychopharmacology. 2019; 44(7): 1328–1334