11C-ORM-13070, a novel PET ligand for brain α2C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men

Luoto, Pauliina; Suilamo, Sami; Oikonen, Vesa; Arponen, Eveliina; Helin, Semi; Herttuainen, Jukka; Hietamäki, Johanna; Holopainen, Aila; Kailajärvi, Marita; Peltonen, Janne; Rouru, Juha; Sallinen, Jukka; Scheinin, Mika; Virta, Jere; Virtanen, Kirsi A.; Volanen, Iina; Roivainen, Anne; Rinne, Juha O.

doi:10.1007/s00259-014-2782-y

Cited by 18 publications

(19 citation statements)

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“…A PET tracer for a 2C adrenoceptors is expected to be useful for preclinical and clinical drug development (20). The tracer has been introduced to human use (21,22), as evidenced by 4 already completed clinical PET trials with 11 C-ORM-13070 (ClinicalTrials. gov identifiers NCT00735774, NCT00829907, NCT01435213, and NCT01794975).…”

Section: Discussionmentioning

confidence: 99%

A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

et al. 2014

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We report the development of a PET tracer for α 2C adrenoceptor imaging and its preliminary preclinical evaluation. α 2C adrenoceptors in the human brain may be involved in various neuropsychiatric disorders, such as depression, schizophrenia, and neurodegenerative diseases. PET tracers are needed for imaging of this receptor system in vivo. Methods: High-specific-activity 11 C-ORM-13070 (1--(3-11 C-methoxymethylpyridin-2-yl)-piperazine) was synthesized by 11 C-methylation of O-desmethyl-ORM-13070 with 11 C-methyl triflate, which was prepared from cyclotron-produced 11 C-methane via 11 C-methyl iodide. Rats and mice were investigated in vivo with PET and ex vivo with autoradiography. The specificity of 11 C-ORM-13070 binding to α 2 adrenoceptors was demonstrated in rats pretreated with atipamezole, an α 2 adrenoceptor antagonist. The α 2C adrenoceptor selectivity of the tracer was determined by comparing tracer binding in wild-type and α 2A -and α 2AC adrenoceptor knockout (KO) mice. 11 C-ORM-13070 and its radioactive metabolites in rat plasma and brain tissue were analyzed with radio-high-performance liquid chromatography and mass spectroscopy. Human radiation dose estimates were extrapolated from rat biodistribution data. Results: The radiochemical yield, calculated from initial cyclotron-produced 11 C-methane, was 9.6% ± 2.7% (decaycorrected to end of bombardment). The specific activity of the product was 640 ± 390 GBq/μmol (decay-corrected to end of synthesis). The radiochemical purity exceeded 99% in all syntheses. The highest levels of tracer binding were observed in the striatum and olfactory tubercle of rats and control and α 2A KO mice-that is, in the brain regions known to contain the highest densities of α 2C adrenoceptors. In rats pretreated with atipamezole and in α 2AC KO mice, 11 C tracer binding in the striatum and olfactory tubercle was low, similar to that of the frontal cortex and thalamus, regions with low densities of α 2C adrenoceptors. Two radioactive metabolites were found in rat plasma, but only one of them was found in the brain; their identity was not revealed. The estimated effective radiation dose was comparable with the average exposure level in PET studies with 11 C tracers. Conclusion: An efficient method for the radiosynthesis of 11 C-ORM-13070 was developed. 11 C-ORM-13070 emerged as a potential novel radiotracer for in vivo imaging of brain α 2C adrenoceptors.

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Section: Discussionmentioning

confidence: 99%

A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

et al. 2014

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“…This compound has a binding affinity selectivity of over 200-fold vs. the α 2A -AR, with weak or no activity at more than 100 other potential target sites and receptors, and will be highly valuable for facilitating forward and reverse translation between animal and human studies. An obvious application is determination of target engagement, through conducting receptor occupancy studies for novel drug candidate molecules for preclinical and clinical studies ( 62 , 245 , 246 ). However, it could also be used to gain more precise insight on the relative α2C -AR occupancy for antipsychotic (e.g., clozapine) and antidepressant (e.g., mirtazapine) agents at clinical doses thus enabling a better understanding on the mode of action of these drugs.…”

Section: Future Perspective: What Do We Have and What Do We Need?mentioning

confidence: 99%

Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia—New Developments and Future Perspective

2017

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α2A- and α2C-adrenoceptors (ARs) are the primary α2-AR subtypes involved in central nervous system (CNS) function. These receptors are implicated in the pathophysiology of psychiatric illness, particularly those associated with affective, psychotic, and cognitive symptoms. Indeed, non-selective α2-AR blockade is proposed to contribute toward antidepressant (e.g., mirtazapine) and atypical antipsychotic (e.g., clozapine) drug action. Both α2C- and α2A-AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA) release, with α2C-AR heteroreceptors regulating non-noradrenergic transmission (e.g., serotonin, dopamine). While the α2A-AR is widely distributed throughout the CNS, α2C-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the α2C-AR plays a more prominent role during states of low endogenous NA activity, while the α2A-AR is relatively more engaged during states of high noradrenergic tone. Although augmentation of conventional antidepressant and antipsychotic therapy with non-selective α2-AR antagonists may improve therapeutic outcome, animal studies report distinct yet often opposing roles for the α2A- and α2C-ARs on behavioral markers of mood and cognition, implying that non-selective α2-AR antagonism may compromise therapeutic utility both in terms of efficacy and side-effect liability. Recently, several highly selective α2C-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the α2C-AR. ORM-13070 is a useful positron emission tomography ligand, ORM-10921 has demonstrated antipsychotic, antidepressant, and pro-cognitive actions in animals, while ORM-12741 is in clinical development for the treatment of cognitive dysfunction and neuropsychiatric symptoms in Alzheimer’s disease. This review will emphasize the importance and relevance of the α2C-AR as a neuropsychiatric drug target in major depression, schizophrenia, and associated cognitive deficits. In addition, we will present new prospects and future directions of investigation.

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“…These studies revealed that [ 11 C]ORM‐13070 penetrated rapidly into the brain with the most prominent accumulation of radioactivity occurring in the caudate nucleus and putamen. The test–retest reliability of the uptake was good, with absolute variability of 4.3% in the putamen and 6.5% in the caudate nucleus (Lehto et al, ; Luoto et al, ).…”

Section: Introductionmentioning

confidence: 99%

Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain

Lehto

Hirvonen²,

Johansson

et al. 2015

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This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies.

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11C-ORM-13070, a novel PET ligand for brain α2C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men

Cited by 18 publications

References 13 publications

A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia—New Developments and Future Perspective

Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain

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11C-ORM-13070, a novel PET ligand for brain α2C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men

Cited by 18 publications

References 13 publications

A PET Tracer for Brain α2C Adrenoceptors, 11C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

A PET Tracer for Brain α2C Adrenoceptors, 11C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia—New Developments and Future Perspective

Validation of [11C]ORM‐13070 as a PET tracer for alpha2c‐adrenoceptors in the human brain

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A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain