Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers
Abstract
Purpose Positron emission tomography (PET) imaging of serotonin 2A (5-HT(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT(2A) receptors in their high-affinity state. We have previously validated [(11)C]Cimbi-5 and found that it is a 5-HT(2A) receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT(2A) receptor agonist PET tracers in the pig brain. Methods Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT(2A) receptor binding, cortical nondisplaceable binding potentials (BP(ND)) were calculated using the simplified reference tissue model with the cerebellum as a reference region. Results After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT(2A) receptor distribution. The largest target-to-background binding ratio was found for [(11)C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [(11)C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT(2A) receptor selectivity in vivo. [(11)C]Cimbi-82 and [(11)C]Cimbi-21 showed lower cortical BP(ND), while [(11)C]Cimbi-27, [(11)C]Cimbi-29, [(11)C]Cimbi-31 and [(11)C]Cimbi-88 gave rise to cortical BP(ND) similar to that of [(11)C]Cimbi-5. Conclusion [(11)C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT(2A) receptor agonist binding in the living human brain with PET.
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The best of the Cimbi series with respect to specific signal and washout from cerebellum was [11C]-Cimbi-36.
“The best of the series with respect to specific signal and washout from cerebellum was [11C]-Cimbi-36 (38).”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [89]
A series of nine structurally similar Cimbi phenethylamine compounds had a ten-fold range in affinity at 5HT2A sites and a 100-fold range in ED50 for activation of IP hydrolysis.
“Furthermore, a series of nine structurally similar compounds of the Cimbi phenethylamine class had a ten-fold range in the affinity at 5HT2A sites and a 100-fold range in their ED50 for activation of IP hydrolysis [89].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [89]
Neither affinity at 5HT2A sites nor ED50 for IP hydrolysis predicted specific binding (BPND) in brain, which ranged from 0.2 to 1.0.
“However, neither property predicted the specific binding (BPND) in brain, which ranged from 0.2 to 1.0.”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [89]
A series of phenylethylamines in the Cimbi series showed Kis in vitro against [3H]-MDL100907 ranging from 0.2 nM (Cimbi-31) to 47 nM (Cimbi-88).
“A series of phenylethyalamines in the Cimbi series showed Kis in vitro against the binding of [3H]-MDL100907 ranging from 0.2 nM (Cimbi-31, 36) to 47 nM (Cimbi-88, 37)”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [89]
Cites
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Nichols, D. E. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.011478 · Cited by 1,762 · see citing works
Serotonin and molecular neuroimaging in humans using PET
Saulin, A., Savli, M., & Lanzenberger, R. (2012) · Amino Acids · doi:10.1007/s00726-011-1078-9 · Cited by 113 · see citing works
Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans.
Cumming, P., Scheidegger, M., Dornbierer, D., Palner, M., Quednow, B. B., & Martin-Soelch, C. (2021) · Molecules · doi:10.3390/molecules26092451 · Cited by 43 · see citing works
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- Authors
- Ettrup, A., Hansen, M., Santini, M. A., Paine, J., Gillings, N., Palner, M., Lehel, S., Herth, M. M., Madsen, J., Kristensen, J., Begtrup, M., & Knudsen, G. M.
- Affiliations
- Copenhagen University Hospital (DK)
- University of Copenhagen (DK)
- Corresponding author
- Knudsen, Gitte M.
- ORCID
- Venue
- European Journal of Nuclear Medicine and Molecular Imaging
- Published
- 2010-12-21
- Volume
- 38
- Issue
- 4
- Pages
- 681-693
- ISSN
- 1619-7070 (ISSN-L)
- 1619-7089
- OpenAlex
- W2133736622
- Cited by
- 128
- References
- 1
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 10 · 2019: 13 · 2018: 4 · 2017: 12 · 2016: 8 · 2015: 13 · 2014: 17 · 2013: 10 · 2012: 4
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Nuclear Medicine and Molecular Imaging (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Lundbeckfonden (R62-2010-5364, R90-2011-7722)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- 5-HT2A receptor, radiotracer synthesis, carbon-11 radiolabeling, ketanserin, pig brain
- MeSH terms
- Animals, Benzylamines, Biological Transport, Brain, Carbon Radioisotopes, Female, Humans, Hydrolysis, Injections, Intravenous, Ketanserin, Phenethylamines, Phosphatidylinositols, Radioactive Tracers, Radiochemistry, Swine, Receptor, Serotonin, 5-HT2A, Positron-Emission Tomography, Serotonin 5-HT2 Receptor Agonists
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