Current radiosynthesis strategies for 5‐HT<sub>2A</sub> receptor PET tracers

Herth, Matthias M.; Knudsen, Gitte M.

doi:10.1002/jlcr.3288

Cited by 17 publications

(15 citation statements)

References 69 publications

(126 reference statements)

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“…([ 11 C]M100907 aka [ 11 C]volinanserin) and [ 18 F]altanserin have been so far the most commonly used antagonist ligands for in vivo PET studies of 5-HT2AR (17)(18)(19). Antagonist ligands bind to the high affinity (HA) and low affinity (LA) conformations of 5-HT2AR with equal affinity (10).…”

Section: C]mdl100907mentioning

confidence: 99%

In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates

et al. 2019

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Purpose: 5-HT2AR exists in high and low affinity states. Agonist PET tracers measure binding to the active high affinity site and thus provide a functionally relevant measure of the receptor. Limited in vivo data have been reported so far for a comparison of agonist versus antagonist tracers for 5-HT2AR used as a proof of principle for measurement of high and low affinity states of this receptor. We compared the in vivo binding of [11C]CIMBI-5, a 5-HT2AR agonist, and of the antagonist [11C]M100907, in monkeys and baboons. Methods: [11C]CIMBI-5 and [11C]M100907 baseline PET scans were performed in anesthetized male baboons (n=2) and male vervet monkeys (n=2) with an ECAT EXACT HR+ and GE 64-slice PET/CT Discovery VCT scanners. Blocking studies were performed in vervet monkeys by pretreatment with MDL100907 (0.5 mg/kg, i.v.) 60 minutes prior to the scan. Regional distribution volumes and binding potentials were calculated for each ROI using the likelihood estimation in graphical analysis and Logan plot, with either plasma input function or reference region as input, and simplified reference tissue model approaches. Results: PET imaging of [11C]CIMBI-5 in baboons and monkeys showed the highest binding in 5-HT2AR-rich cortical regions, while the lowest binding was observed in cerebellum, consistent with the expected distribution of 5-HT2AR. Very low free fractions and rapid metabolism were observed for [11C]CIMBI-5 in baboon plasma. Binding potential values for [11C]CIMBI-5 were 25-33% lower than those for [11C]MDL100907 in the considered brain regions. Conclusion: The lower binding potential of [11C]CIMBI-5 in comparison to [11C]MDL100907 is likely due to the preferential binding of the former to the high affinity site in vivo in contrast to the antagonist, [11C]MDL100907, which binds to both high and low affinity sites.

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Section: C]mdl100907mentioning

confidence: 99%

In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates

et al. 2019

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“…Besides its influence on numerous physiological functions, the 5-HT 2A receptor is believed to be involved in the pathophysiology of several neurological and psychiatric disorders including depression, anxiety disorders, personality disorders, obsessive-compulsive disorder, bipolar disorder, Alzheimer’s disease and schizophrenia [2, 5–13]. Positron emission tomography (PET) is an interesting tool in brain imaging research, permitting the visualization of the 5-HT 2A receptor in the living brain by using receptor specific radioligands [14–16]. In vivo study of this receptor is an important field of research as it improves our understanding of the various diseases in which the receptor is implicated.…”

Section: Introductionmentioning

confidence: 99%

Kinetic analysis of [18F] altanserin bolus injection in the canine brain using PET imaging

et al. 2019

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BackgroundCurrently, [18F] altanserin is the most frequently used PET-radioligand for serotonin2A (5-HT2A) receptor imaging in the human brain but has never been validated in dogs. In vivo imaging of this receptor in the canine brain could improve diagnosis and therapy of several behavioural disorders in dogs. Furthermore, since dogs are considered as a valuable animal model for human psychiatric disorders, the ability to image this receptor in dogs could help to increase our understanding of the pathophysiology of these diseases. Therefore, five healthy laboratory beagles underwent a 90-min dynamic PET scan with arterial blood sampling after [18F] altanserin bolus injection. Compartmental modelling using metabolite corrected arterial input functions was compared with reference tissue modelling with the cerebellum as reference region.ResultsThe distribution of [18F] altanserin in the canine brain corresponded well to the distribution of 5-HT2A receptors in human and rodent studies. The kinetics could be best described by a 2-Tissue compartment (2-TC) model. All reference tissue models were highly correlated with the 2-TC model, indicating compartmental modelling can be replaced by reference tissue models to avoid arterial blood sampling.ConclusionsThis study demonstrates that [18F] altanserin PET is a reliable tool to visualize and quantify the 5-HT2A receptor in the canine brain.

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“…The serotonin‐2A receptor (5‐HT 2A R) has been identified to be involved in the pathophysiology of psychiatric disorders, including schizophrenia and depression . Pharmacological intervention with 5‐HT 2A R acting compounds suggests that the receptor could be a target for several different purposes, eg, hypnotics such as trazodone requiring 5‐HT 2A R antagonism for therapeutic action . Additionally, the 5‐HT 2A R is a key target for second‐generation neuroleptics, with drugs (eg clozapine) again relying on the antagonism of the receptor .…”

Section: Introductionmentioning

confidence: 99%

“…1,2 Pharmacological intervention with 5-HT 2A R acting compounds suggests that the receptor could be a target for several different purposes, eg, hypnotics such as trazodone requiring 5-HT 2A R antagonism for therapeutic action. [3][4][5][6][7] Additionally, the 5-HT 2A R is a key target for second-generation neuroleptics, with drugs (eg clozapine) again relying on the antagonism of the receptor. 8 Positron emission tomography (PET) is a powerful tool for molecular imaging allowing in vivo studies and visualisation of human physiology.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, radiofluorination, and preliminary evaluation of the potential 5‐HT_2A receptor agonists [¹⁸F]Cimbi‐92 and [¹⁸F]Cimbi‐150

Edgar

Hansen²,

Leth-Petersen

et al. 2017

Labelled Comp Radiopharmac

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An agonist PET tracer is of key interest for the imaging of the 5-HT receptor, as exemplified by the previously reported success of [ C]Cimbi-36. Fluorine-18 holds several advantages over carbon-11, making it the radionuclide of choice for clinical purposes. In this respect, an F-labelled agonist 5-HT receptor (5-HT R) tracer is highly sought after. Herein, we report a 2-step, 1-pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5-HT R. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled in acceptable radiochemical yields, sufficient for in vivo studies in domestic pigs. PET images partially conformed to the expected brain distribution of the 5-HT R; a notable exception however being significant uptake in the striatum and thalamus. Additionally, a within-scan displacement challenge with a 5-HT R antagonist was unsuccessful, indicating that the tracers cannot be considered optimal for neuroimaging of the 5-HT R.

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Current radiosynthesis strategies for 5‐HT_2A receptor PET tracers

Cited by 17 publications

References 69 publications

In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates

In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates

Kinetic analysis of [18F] altanserin bolus injection in the canine brain using PET imaging

Synthesis, radiofluorination, and preliminary evaluation of the potential 5‐HT_2A receptor agonists [¹⁸F]Cimbi‐92 and [¹⁸F]Cimbi‐150

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Current radiosynthesis strategies for 5‐HT2A receptor PET tracers

Cited by 17 publications

References 69 publications

In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates

In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates

Kinetic analysis of [18F] altanserin bolus injection in the canine brain using PET imaging

Synthesis, radiofluorination, and preliminary evaluation of the potential 5‐HT2A receptor agonists [18F]Cimbi‐92 and [18F]Cimbi‐150

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Current radiosynthesis strategies for 5‐HT_2A receptor PET tracers

Synthesis, radiofluorination, and preliminary evaluation of the potential 5‐HT_2A receptor agonists [¹⁸F]Cimbi‐92 and [¹⁸F]Cimbi‐150