Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers

@article{Ettrup2010RadiosynthesisAI,
  title={Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers},
  author={Anders Ettrup and Martin Hansen and Martin A. Santini and James Paine and Nic Gillings and Mikael Palner and Szabolcs Lehel and Matthias Manfred Herth and Jacob Madsen and Jesper L. Kristensen and Mikael Begtrup and Gitte Moos Knudsen},
  journal={European Journal of Nuclear Medicine and Molecular Imaging},
  year={2010},
  volume={38},
  pages={681-693}
}
PurposePositron emission tomography (PET) imaging of serotonin 2A (5-HT2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT2A receptors in their high-affinity state. We have previously validated [11C]Cimbi-5 and found that it is a 5-HT2A 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 [11C]Cimbi-5 in different… 
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Preclinical Safety Assessment of the 5-HT2A Receptor Agonist PET Radioligand [11C]Cimbi-36
TLDR
Administration of tracer doses of [11C]Cimbi-36 does not seem to be associated with unusual radiation burden or adverse clinical effects, and the estimated absorbed radiation dose to human target organs did not exceed safety levels.
Synthesis, radiofluorination, and preliminary evaluation of the potential 5-HT2A receptor agonists [18 F]Cimbi-92 and [18 F]Cimbi-150.
TLDR
A 2-step, 1-pot labelling methodology of 2 tracer candidates, synthesised from easily accessible labelling precursors, and radiolabelled in acceptable radiochemical yields, sufficient for in vivo studies in domestic pigs are reported.
Radiosynthesis and Biological Evaluation of [18F]R91150, a Selective 5-HT2A Receptor Antagonist for PET-Imaging.
TLDR
Autoradiographic studies with [18F]R91150 in rat brain slices revealed the typical uptake pattern of 5-HT2A receptor ligands, and the total synthesis time was reduced to 60 min.
Convergent 18F-labeling and evaluation of N-benzyl-phenethylamines as 5-HT2A receptor PET ligands.
TLDR
A convergent radiochemical approach is developed giving easy access to 5 different 18F-labeled ligands structurally related to Cimbi-36 from a common 18F -labeled intermediate, which seems unsuitable for neuroimaging of the 5-HT2AR in vivo.
Human biodistribution and radiation dosimetry of the 5-HT2A receptor agonist Cimbi-36 labeled with carbon-11 in two positions
TLDR
The biodistribution of Cimbi-36 (and its metabolites) may also help to shed light on the toxic effects of 25B-NBOMe when used in pharmacological doses in recreational settings.
Synthesis and evaluation of (18)F-labeled 5-HT2A receptor agonists as PET ligands.
TLDR
It is suggested that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist.
Characterization of [11C]Cimbi-36 as an agonist PET radioligand for the 5-HT2A and 5-HT2C receptors in the nonhuman primate brain
TLDR
The receptor binding of [(11)C]Cimbi-36 can be quantified using kinetic modeling and the cerebellum was found to be a suitable reference region and the two-tissue compartment model was superior for the description of the time-radioactivity curves of all examined brain regions.
In vivo evaluation of [18F]FECIMBI-36, an agonist 5-HT2A/2C receptor PET radioligand in nonhuman primate.
TLDR
Although the time activity curves indicate a somehow heterogeneous distribution of the radioligand in the brain, the low level of [18F]FECIMBI-36 in brain may limit the use of this tracer for quantification of 5-HT2A/2C receptors by PET.
The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [11C]Cimbi-36 labeled in two positions
  • A. Johansen, H. D. Hansen, +5 authors G. Knudsen
  • Chemistry, Medicine
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
  • 2018
TLDR
It is shown that small polar radiometabolites can substantially decrease the signal-to- Background ratio of PET radioligands for neuroimaging, and it is found that [11C]Cimbi-36 has a better signal- to-background ratio, and thus will be more sensitive to changes in 5-HT2A receptor levels in the brain.
Serotonin 2A Receptor Agonist Binding in the Human Brain with [11C]Cimbi-36
  • A. Ettrup, Sophie da Cunha-Bang, +12 authors G. Knudsen
  • Chemistry, Medicine
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
  • 2014
TLDR
Cimbi-36 is described as the first agonist PET radioligand to successfully image and quantify 5-HT2A receptors in the human brain.
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References

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Radiosynthesis and Evaluation of 11C-CIMBI-5 as a 5-HT2A Receptor Agonist Radioligand for PET
TLDR
11C-CIMBI-5 is a promising tool for investigation of 5-HT2A agonist binding in the living human brain and has a sufficient target-to-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs.
Evaluation of the Novel 5-HT4 Receptor PET Ligand [11C]SB207145 in the Göttingen Minipig
TLDR
It is found that in the minipig brain [11C]SB207145 follows one-tissue compartment kinetics, and the simplified reference tissue model provides stable and precise estimates of the binding potential in all regions, where PET-measurements significantly underestimate the 5-HT4 receptor binding.
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TLDR
This preliminary study suggests that [11C]MDL 100,907 is a suitable PET radioligand for studies on 5-HT2A receptors in man, and is recommended in the future for PET studies in healthy subjects and schizophrenic patients, including the determination of drug-induced 5- HT2A receptor occupancy.
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TLDR
It is concluded that 5-HT2A receptor studies can be conducted within 2 h of [18F]altanserin infusion, yielding reliable results.
Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses
TLDR
NIGA is well suited for analysis of [(11)C]MDL100,907 PET studies, yielding estimates of 5-HT(2A) receptor availability and changes that are highly correlated with results from invasive 2TCM analyses, which should greatly enhance the applicability of 5/2A receptor PET studies.
A Comparative Evaluation of the Dopamine D2/3 Agonist Radiotracer [11C](−)-N-Propyl-norapomorphine and Antagonist [11C]Raclopride to Measure Amphetamine-Induced Dopamine Release in the Human Striatum
TLDR
Results suggest that [ 11C]NPA is more vulnerable to endogenous competition by dopamine compared with [11C]raclopride by a factor of 1.49 to 1.90, which adds to the growing literature that suggests D2/3 agonist radiotracers are more vulnerable than existing D 2/3 antagonist radiotacers.
Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET.
TLDR
Interestingly, compounds MA-1 (53), MH.MZ (55) and (R-MH) provide a receptor selectivity profile similar to MDL 100907 and appear to be promising high affine and selective tracers of (18)F-labelled analogues for 5-HT(2A) imaging with PET.
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TLDR
The aim of this study was to compare binding characteristics of these two radiotracers in rat brain with respect to affinity, receptor binding density, binding potential, and nonspecific binding.
Measuring Endogenous 5-HT Release by Emission Tomography: Promises and Pitfalls
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  • Psychology, Medicine
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
  • 2010
TLDR
Suggestions are made as to how the selection of targets, radiotracers, challenge paradigms, and experimental design might be optimised to improve the chances of successfully imaging endogenous neurotransmitters in the future.
In vivo vulnerability to competition by endogenous dopamine: Comparison of the D2 receptor agonist radiotracer (–)‐N‐[11C]propyl‐norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]‐raclopride
TLDR
Results suggest that 71% of D2 receptors are configured in a state of high affinity for agonists in vivo, and [11C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease.
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