11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements

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

doi:http://dx.doi.org/10.2967/jnumed.111.088815

11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements

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

45 Citations (Scopus)

Abstract

Small-molecule α₇ nicotinic acetylcholine receptor (α₇nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α₇nAChR PET tracer would be important for in vivo quantification of α₇nAChR binding in humans and to measure α₇nAChR occupancy of α₇nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of ¹¹C-NS14492 as a selective α₇nAChR PET radioligand. Methods: The high-affinity α₇nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using ¹¹C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the α₇nAChR partial agonist SSR180711 or the unlabeled NS14492. ¹¹C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; ¹¹C-NS14492 regional distribution volumes were calculated, and α₇nAChR occupancy was determined using an occupancy plot. Results: ¹¹C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α₇nAChR distribution. Pre-treatment with NS14492 and SSR180711 consistently decreased distribution volumes of ¹¹C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α₇nAChR in vivo. Conclusion: We report here that ¹¹C-NS14492 is the first, to our knowledge, PET radioligand for α₇nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of α₇nAChR binding in the human brain.

Original language	English
Journal	Journal of Nuclear Medicine
Volume	52
Issue number	9
Pages (from-to)	1449-56
Number of pages	8
ISSN	0161-5505
DOIs	https://doi.org/10.2967/jnumed.111.088815
Publication status	Published - 1 Sept 2011

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Ettrup, A., Mikkelsen, J. D., Lehel, S., Madsen, J., Nielsen, E. Ø., Palner, M., Timmermann, D. B., Peters, D., & Knudsen, G. M. (2011). 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements. Journal of Nuclear Medicine, 52(9), 1449-56. https://doi.org/10.2967/jnumed.111.088815

11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements. / Ettrup, Anders; Mikkelsen, Jens D; Lehel, Szabolcs et al.

In: Journal of Nuclear Medicine, Vol. 52, No. 9, 01.09.2011, p. 1449-56.

Research output: Contribution to journal › Journal article › Research › peer-review

Ettrup, A, Mikkelsen, JD, Lehel, S, Madsen, J, Nielsen, EØ, Palner, M, Timmermann, DB, Peters, D & Knudsen, GM 2011, '11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements', Journal of Nuclear Medicine, vol. 52, no. 9, pp. 1449-56. https://doi.org/10.2967/jnumed.111.088815

@article{5c2b5fd4bd6a4cbf98494c24a683e40f,

title = "11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements",

abstract = "Small-molecule α7 nicotinic acetylcholine receptor (α7nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α7nAChR PET tracer would be important for in vivo quantification of α7nAChR binding in humans and to measure α7nAChR occupancy of α7nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of 11C-NS14492 as a selective α7nAChR PET radioligand. Methods: The high-affinity α7nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using 11C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the α7nAChR partial agonist SSR180711 or the unlabeled NS14492. 11C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; 11C-NS14492 regional distribution volumes were calculated, and α7nAChR occupancy was determined using an occupancy plot. Results: 11C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α7nAChR distribution. Pre-treatment with NS14492 and SSR180711 consistently decreased distribution volumes of 11C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α7nAChR in vivo. Conclusion: We report here that 11C-NS14492 is the first, to our knowledge, PET radioligand for α7nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of α7nAChR binding in the human brain.",

author = "Anders Ettrup and Mikkelsen, {Jens D} and Szabolcs Lehel and Jacob Madsen and Nielsen, {Elsebet {\O}} and Mikael Palner and Timmermann, {Daniel B} and Dan Peters and Knudsen, {Gitte M}",

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T1 - 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements

AU - Ettrup, Anders

AU - Mikkelsen, Jens D

AU - Lehel, Szabolcs

AU - Madsen, Jacob

AU - Nielsen, Elsebet Ø

AU - Palner, Mikael

AU - Timmermann, Daniel B

AU - Peters, Dan

AU - Knudsen, Gitte M

PY - 2011/9/1

Y1 - 2011/9/1

N2 - Small-molecule α7 nicotinic acetylcholine receptor (α7nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α7nAChR PET tracer would be important for in vivo quantification of α7nAChR binding in humans and to measure α7nAChR occupancy of α7nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of 11C-NS14492 as a selective α7nAChR PET radioligand. Methods: The high-affinity α7nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using 11C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the α7nAChR partial agonist SSR180711 or the unlabeled NS14492. 11C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; 11C-NS14492 regional distribution volumes were calculated, and α7nAChR occupancy was determined using an occupancy plot. Results: 11C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α7nAChR distribution. Pre-treatment with NS14492 and SSR180711 consistently decreased distribution volumes of 11C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α7nAChR in vivo. Conclusion: We report here that 11C-NS14492 is the first, to our knowledge, PET radioligand for α7nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of α7nAChR binding in the human brain.

AB - Small-molecule α7 nicotinic acetylcholine receptor (α7nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α7nAChR PET tracer would be important for in vivo quantification of α7nAChR binding in humans and to measure α7nAChR occupancy of α7nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of 11C-NS14492 as a selective α7nAChR PET radioligand. Methods: The high-affinity α7nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using 11C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the α7nAChR partial agonist SSR180711 or the unlabeled NS14492. 11C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; 11C-NS14492 regional distribution volumes were calculated, and α7nAChR occupancy was determined using an occupancy plot. Results: 11C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α7nAChR distribution. Pre-treatment with NS14492 and SSR180711 consistently decreased distribution volumes of 11C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α7nAChR in vivo. Conclusion: We report here that 11C-NS14492 is the first, to our knowledge, PET radioligand for α7nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of α7nAChR binding in the human brain.

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DO - http://dx.doi.org/10.2967/jnumed.111.088815

M3 - Journal article

SN - 0161-5505

VL - 52

SP - 1449

EP - 1456

JO - The Journal of Nuclear Medicine

JF - The Journal of Nuclear Medicine

IS - 9

ER -

11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements

Abstract

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