<sup>11</sup>C-NS14492 as a Novel PET Radioligand for Imaging Cerebral α7 Nicotinic Acetylcholine Receptors: In Vivo Evaluation and Drug Occupancy Measurements

Ettrup, Anders; Mikkelsen, Jens D.; Lehel, Szabolcs; Madsen, Jacob; Nielsen, Elsebet Ø.; Palner, Mikael; Timmermann, Daniel B.; Peters, Dan; Knudsen, Gitte M.

doi:10.2967/jnumed.111.088815

Cited by 60 publications

(46 citation statements)

References 31 publications

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“…As described above, the most reliable labeling strategies are the use of a7 nAChR-specific radiolabeled ligands such as a-Btx, MLA, A-585539, CHIBA-1001, AZ11637326, A-582941, A-844606, NS14492, or NS14490 (Han et al, 2003;Tribollet et al, 2004;Anderson et al, 2008;Hashimoto et al, 2008;Toyohara et al, 2010;Ettrup et al, 2011;Maier et al, 2011;Rötering et al, 2014). An alternative approach is to detect a7 nAChR expression levels by measuring the levels of CHRNA7 mRNA, as was performed in monkey brain (Han et al, 2000) and in post mortem human brain (Breese et al, 1997).…”

Section: G Expression and Function Of A7 Nicotinic Acetylcholine Recmentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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Section: G Expression and Function Of A7 Nicotinic Acetylcholine Recmentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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“…This ratio of specific-to-nonspecific binding is larger than what is obtained by other PET ligands evaluated in the same species, for example, approximately 50% for 11 C-NS14492 and approximately 35% for 11 C-SB2047145 (19,29).…”

Section: Discussionmentioning

confidence: 67%

Radiosynthesis and In Vivo Evaluation of Novel Radioligands for PET Imaging of Cerebral 5-HT₇ Receptors

et al. 2014

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The serotonin (5-hydroxytryptamine [5-ΗΤ]) 7 receptor (5-HT 7 R) is the most recently discovered 5-HT receptor, and its physiologic and possible pathophysiologic roles are not fully elucidated. So far, no suitable 5-HT 7 R PET radioligand is available, thus limiting the investigation of this receptor in the living brain. Here, we present the radiosynthesis and in vivo evaluation of piperazine-1-yl]butyl}p-1,3-dihydro-2H-indol-2-one) and piperazine-1-yl]butyl}-1,3-dihydro-2H-indol-2-one) as selective 5-HT 7 R PET radioligands in the pig brain. The 5-HT 7 R distribution in the postmortem pig brain is also assessed. Methods: In vitro autoradiography with the 5-HT 7 R selective radioligand 3 H-labeled (R)-3-(2-(2-(4-methylpiperidin-1-yl) ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) was performed on pig brain sections to establish the 5-HT 7 R binding distribution. Radiolabeling of 5-HT 7 R selective compounds was performed in an automated synthesis module in which we conducted either palladiummediated cross coupling ( 11 C-Cimbi-712) or conventional O-methylation ( 11 C-Cimbi-717) using 11 C-MeI and 11 C-MeOTf, respectively. After intravenous injection of the radioligands in Danish Landrace pigs, the in vivo brain distribution of the ligands was studied. Specific binding of 11 C-Cimbi-712 and 11 C-Cimbi717 to 5-HT 7 R was investigated by intravenous administration of SB-269970 before a second PET scan. Results: High 5-HT 7 R density was found in the thalamus and cortical regions of the pig brain by autoradiography. The radiosynthesis of both radioligands succeeded after optimization efforts (radiochemical yield, ∼20%-30% at the end of synthesis). Timeactivity curves of 11 C-Cimbi-712 and 11 C-Cimbi-717 showed high brain uptake and distribution according to 5-HT 7 R distribution, but the tracer kinetics of 11 C-Cimbi-717 were faster than 11 C-Cimbi-712. Both radioligands were specific for 5-HT 7 R, as binding could be blocked by pretreatment with SB-269970 for 11 C-Cimbi-717 in a dose-dependent fashion. For 11 C-Cimbi-717, nondisplaceable binding potentials of 6.4 ± 1.2 (n 5 6) were calculated in the thalamus. Conclusion: Both 11 C-Cimbi-712 and 11 C-Cimbi-717 generated a specific binding in accordance with 5-HT 7 R distribution and are potential PET radioligands for 5-HT 7 R. 11 C-Cimbi-717 is the better candidate because of the more reversible tracer kinetics, and this radioligand showed a dose-dependent decline in cerebral binding after receptor blockade. Thus, 11 C-Cimbi-717 is currently the most promising radioligand for investigation of 5-HT 7 R binding in the living human brain. The serotonergic system plays a key modulatory role in the brain and is a target for many drug treatments for brain disorders either through reuptake blockade or interactions with one or more of the 14 subtypes of 5-hydroxytryptamine (5-HT) receptors. Our knowledge about the behavior of the 5-HT system in vivo is still scattered, and most of the understanding is derived from animal models. However, the use of imaging techniques such...

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“…It was radiolabelled with 11 C and investigated in pigs, where the radioligand showed the capability of measuring in vivo occupancy at 7 nAChR (Ettrup et al, 2010). With regard to molecular imaging, the development of quantitative approaches to visualise 7 nAChR outside the brain is another big challenge because comparably low receptor densities have to be expected also in peripheral organs.…”

Section: Noninvasive Imaging Of 7 Nachr In Other Diseases -Reality Amentioning

confidence: 99%

Molecular Imaging of 7 Nicotinic Acetylcholine Receptors In Vivo: Current Status and Perspectives

Brust¹,

Deuther‐Conrad²

2012

Neuroimaging - Clinical Applications

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¹¹C-NS14492 as a Novel PET Radioligand for Imaging Cerebral α7 Nicotinic Acetylcholine Receptors: In Vivo Evaluation and Drug Occupancy Measurements

Cited by 60 publications

References 31 publications

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Radiosynthesis and In Vivo Evaluation of Novel Radioligands for PET Imaging of Cerebral 5-HT₇ Receptors

Molecular Imaging of 7 Nicotinic Acetylcholine Receptors In Vivo: Current Status and Perspectives

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11C-NS14492 as a Novel PET Radioligand for Imaging Cerebral α7 Nicotinic Acetylcholine Receptors: In Vivo Evaluation and Drug Occupancy Measurements

Cited by 60 publications

References 31 publications

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Radiosynthesis and In Vivo Evaluation of Novel Radioligands for PET Imaging of Cerebral 5-HT7 Receptors

Molecular Imaging of 7 Nicotinic Acetylcholine Receptors In Vivo: Current Status and Perspectives

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¹¹C-NS14492 as a Novel PET Radioligand for Imaging Cerebral α7 Nicotinic Acetylcholine Receptors: In Vivo Evaluation and Drug Occupancy Measurements

Radiosynthesis and In Vivo Evaluation of Novel Radioligands for PET Imaging of Cerebral 5-HT₇ Receptors