Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain

Yang, Kai-Chun; Степанов, В. А.; Martinsson, Stefan; Ettrup, Anders; Takano, Akihiro; Knudsen, Gitte M.; Halldin, Christer; Farde, Lars; Finnema, Sjoerd J.

doi:10.1093/ijnp/pyx051

Cited by 24 publications

(29 citation statements)

References 51 publications

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“…Imaging of the 5-HT 2A R subtype is well established through antagonist tracers such as 18 F-seperone and 18 Faltanserine, with differences in receptor density identified in patients with obsessive-compulsive disorder [252], Tourette's syndrome [253], schizophrenia [254], and AD [255]. However, while able to report on receptor density, 5-HT 2A antagonist tracers are unable to distinguish between the high-and low-affinity states of 5-HT 2A and are relatively insensitive to endogenous neurotransmitter concentration [256,257]. As such abnormalities related to the 5-HT 2A high/low-affinity ratio or serotonin levels are unable to be identified using these tracers.…”

Section: Serotonin 5-ht 2 Rmentioning

confidence: 99%

“…In both human and NHP blocking, studies with 5-HT 2 R antagonist ketanserin (non-selective between 5-HT 2 subcategories A-C) showed significant reduction across the brain (Table 3) [103,104]. Pre-clinical studies have shown a significant response to pharmacologically increased and decreased levels of serotonin in vivo in NHP and rodents respectively showing the potential sensitivity of 11 C-Cimbi-36 to endogenous neurotransmitter concentration [257,259].…”

Section: Selectivity Data For 11 C-cimbi-36mentioning

confidence: 99%

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Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

McCluskey

Plisson

Rabiner

et al. 2019

Eur J Nucl Med Mol Imaging

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Purpose A limit on developing new treatments for a number of central nervous system (CNS) disorders has been the inadequate understanding of the in vivo pathophysiology underlying neurological and psychiatric disorders and the lack of in vivo tools to determine brain penetrance, target engagement, and relevant molecular activity of novel drugs. Molecular neuroimaging provides the tools to address this. This article aims to provide a state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for inhuman imaging. Methods We provide an overview of the criteria used to evaluate PET tracers. We then used the National Institute of Mental Health Research Priorities list to identify the key CNS targets. We conducted a PubMed search (search period 1st of January 2013 to 31st of December 2018), which yielded 40 new PET tracers across 16 CNS targets which met our selectivity criteria. For each tracer, we summarised the evidence of its properties and potential for use in studies of CNS pathophysiology and drug evaluation, including its target selectivity and affinity, inter and intra-subject variability, and pharmacokinetic parameters. We also consider its potential limitations and missing characterisation data, but not specific applications in drug development. Where multiple tracers were present for a target, we provide a comparison of their properties. Results and conclusions Our review shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others. Some of the most promising of these include 18 F-MK-6240 for tau imaging, 11 C-UCB-J for imaging SV2A, 11 C-CURB and 11 C-MK-3168 for characterisation of fatty acid amide hydrolase, 18 F-FIMX for metabotropic glutamate receptor 1, and 18 F-MNI-444 for imaging adenosine 2A. Our review also identifies recurrent issues within the field. Many of the tracers discussed lack in vivo blocking data, reducing confidence in selectivity. Additionally, late-stage identification of substantial off-target sites for multiple tracers highlights incomplete preclinical characterisation prior to translation, as well as human disease state studies carried out without confirmation of test-retest reproducibility.

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Section: Serotonin 5-ht 2 Rmentioning

confidence: 99%

Section: Selectivity Data For 11 C-cimbi-36mentioning

confidence: 99%

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

McCluskey

Plisson

Rabiner

et al. 2019

Eur J Nucl Med Mol Imaging

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“…Competitive binding assay from the Psychoactive Drug Screening Program (PDSP) of the National Institute of Mental Health (NIMH) shows that CIMBI-5 has equivalent affinity to 5-HT2BR and a threefold higher affinity to 5-HT2CR than to 5-HT2AR and did not have significant affinity for various other brain targets (24). Recently, [ 11 C]CIMBI-36 (Ki = 0.5 nM, Emax = 87%), the bromo-analogue of CIMBI-5, has been reported to have comparable specific to non-specific binding ratio as of [ 11 C]CIMBI-5 in pig and nonhuman primates; including receptor occupancy in pig brain and fenfluramine induced endogenous changes in monkeys (28)(29)(30)(31). Subsequently, [ 11 C]CIMBI-36 has been studied in human and thus it is so far the only 5-HT2AR agonist PET tracer studied in human (32).…”

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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“…By contrast, agonist tracers should only bind to the active receptor pool and may thus provide additional information regarding neurotransmission . In this respect, agonists should be more sensitive to endogenous serotonin, and as a consequence agonists could serve as a tool to quantify endogenous serotonin concentrations within the synaptic cleft . Furthermore, agonist tracers should provide a better estimate of receptor occupancy levels of receptor activating therapeutic drugs .…”

Section: Introductionmentioning

confidence: 99%

“…23 In this respect, agonists should be more sensitive to endogenous serotonin, and as a consequence agonists could serve as a tool to quantify endogenous serotonin concentrations within the synaptic cleft. 24,25 Furthermore, agonist tracers should provide a better estimate of receptor occupancy levels of receptor activating therapeutic drugs. 26 Access to a 5-HT 2A R agonist PET tracer could provide insights into therapeutic mechanism of action, the effects on neurobiology and potentially help determine effective doses of similar drugs.…”

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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Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain

Cited by 24 publications

References 51 publications

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

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

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

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Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain

Cited by 24 publications

References 51 publications

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

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

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

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