Direct comparison of [18F]MH.MZ and [18F]altanserin for 5‐HT2A receptor imaging with PET

Hansen, Hanne D.; Ettrup, Anders; Herth, Matthias M.; Dyssegaard, Agnete; Ratner, Cecilia; Gillings, Nic; Knudsen, Gitte M.

doi:10.1002/syn.21643

Cited by 20 publications

(21 citation statements)

References 31 publications

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“…11 This can be attributed to a relatively high concentration of 5-HT 2A receptors in the pig cerebellum which was also recently described. 31 In summary, we have shown that the novel receptor agonist PET radioligand, …”

Section: Resultsmentioning

confidence: 87%

Serotonin 2A Receptor Agonist Binding in the Human Brain with [¹¹C]Cimbi-36

Ettrup

Cunha-Bang

McMahon

et al. 2014

J Cereb Blood Flow Metab

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111

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[ 11 C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT 2A ) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with INTRODUCTIONThe neurotransmitter serotonin (5-HT) is a modulator of a vast variety of normal physiologic effects and is also involved in the pathophysiology of central nervous system disorders such as depression and schizophrenia. The serotonin 2A (5-HT 2A ) receptor is the main excitatory 5-HT receptor in the human central nervous system, it is responsible for the hallucinogenic effects of recreational agonist drugs such as lysergic acid diethylamide and psilocybin, and 5-HT 2A receptor antagonism is a characteristic of atypical antipsychotics. 1 Furthermore, changes in 5-HT 2A receptor levels have been linked to the pathophysiology of human diseases such as depression. 2,3 Positron emission tomography (PET) has unsurpassed sensitivity and selectivity to detect and quantify specific proteins and processes in the human brain. Positron emission tomography imaging with radioligands is a widely used tool to quantify differences in receptor binding, for example, between patient and control groups, to quantify receptor occupancy of pharmacological interventions or to measure neurotransmitter release in vivo. 4,5 In clinical studies, 5-HT 2A receptor antagonists have for decades been in use as PET radioligands, most notably [ 18 F]altanserin and [ 11 C]MDL100907. 6 However, agonist PET radioligands may functionally possess several advantages over antagonists. Importantly, agonist radioligands in the dopamine system have an increased sensitivity to endogenously released neurotransmitter. Here, several studies using pharmacologically increased dopamine

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Section: Resultsmentioning

confidence: 87%

Serotonin 2A Receptor Agonist Binding in the Human Brain with [¹¹C]Cimbi-36

Ettrup

Cunha-Bang

McMahon

et al. 2014

J Cereb Blood Flow Metab

Self Cite

111

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“…Two groups reported [ 18 F]fluoroethyl-M100907 ([ 18 F]FEM100907 aka [ 18 F]MH.MZ), a fluoroethyl analogue of M100907 with faster off-rate than [ 11 C]M100907 [110,111]. [ 18 F]MH.MZ has higher cortex to cerebellum ratio in nonhuman primates and pigs [112]. Further studies are required to establish the utility of [ 18 F]MH.MZ in human studies.…”

Section: Introductionmentioning

confidence: 99%

PET Tracers for Serotonin Receptors and Their Applications

Js¹,

Mann

2015

CNSAMC

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Serotonin receptors (5-HTRs) are implicated in the pathophysiology of a variety of neuropsychiatric and neurodegenerative disorders and are also targets for drug therapy. In the CNS, most of these receptors are expressed in high abundance in specific brain regions reflecting their role in brain functions. Quantifying binding to 5-HTRs in vivo may permit assessment of physiologic and pathologic conditions, and monitoring disease progression, evaluating treatment response, and for investigating new treatment modalities. Positron emission tomography (PET) molecular imaging has the sensitivity to quantify binding of 5-HTRs in CNS disorders and to measure drug occupancy as part of a process of new drug development. Although research on PET imaging of 5-HTRs have been performed more than two decades, the successful radiotracers so far

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“…To test whether this is the case, a displacement study with the known 5‐HT 2A R antagonist ketanserin was conducted. The experimental setup used within this study has previously been successfully applied in the same animal model for [ 11 C]Cimbi‐36 or [ 18 F]MH.MZ . The displacement study was performed after 90 minutes.…”

Section: Resultsmentioning

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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Direct comparison of [¹⁸F]MH.MZ and [¹⁸F]altanserin for 5‐HT_2A receptor imaging with PET

Cited by 20 publications

References 31 publications

Serotonin 2A Receptor Agonist Binding in the Human Brain with [¹¹C]Cimbi-36

Serotonin 2A Receptor Agonist Binding in the Human Brain with [¹¹C]Cimbi-36

PET Tracers for Serotonin Receptors and Their Applications

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

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Direct comparison of [18F]MH.MZ and [18F]altanserin for 5‐HT2A receptor imaging with PET

Cited by 20 publications

References 31 publications

Serotonin 2A Receptor Agonist Binding in the Human Brain with [11C]Cimbi-36

Serotonin 2A Receptor Agonist Binding in the Human Brain with [11C]Cimbi-36

PET Tracers for Serotonin Receptors and Their Applications

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

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Direct comparison of [¹⁸F]MH.MZ and [¹⁸F]altanserin for 5‐HT_2A receptor imaging with PET

Serotonin 2A Receptor Agonist Binding in the Human Brain with [¹¹C]Cimbi-36

Serotonin 2A Receptor Agonist Binding in the Human Brain with [¹¹C]Cimbi-36

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