The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [11C]Cimbi-36 labeled in two positions

Annette Johansen; Hanne D Hansen; Claus Svarer; Szabolcs Lehel; Sebastian Leth-Petersen; Jesper L Kristensen; Nic Gillings; Gitte M Knudsen

doi:10.1177/0271678x17746179

The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [¹¹C]Cimbi-36 labeled in two positions

Annette Johansen, Hanne D Hansen, Claus Svarer, Szabolcs Lehel, Sebastian Leth-Petersen, Jesper L Kristensen, Nic Gillings, Gitte M Knudsen

Department of Clinical Medicine

13 Citations (Scopus)

Abstract

[11C]Cimbi-36, a 5-HT2A receptor agonist PET radioligand, contains three methoxy groups amenable to [11C]-labeling. In pigs, [11C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [11C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [11C]Cimbi-36 eliminates M2 in humans, and if this changes the signal-to-background ratio. Six healthy volunteers each underwent two dynamic PET scans; after injection of [11C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [11C]Cimbi-36_5 injection. [11C]Cimbi-36_5 generated higher uptake than [11C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [11C]Cimbi-36 was 1.38 ± 0.07, whereas for [11C]Cimbi-36_5, it was 1.18 ± 0.14. This significant difference can be explained by higher non-displaceable binding caused by demethylation products in the M1 fraction such as [11C]formaldehyde and/or [11C]carbon dioxide/bicarbonate. Although often considered without any impact on binding measures, we show that small polar radiometabolites can substantially decrease the signal-to-background ratio of PET radioligands for neuroimaging. Further, we find that [11C]Cimbi-36 has a better signal-to-background ratio than [11C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT2A receptor levels in the brain.

Original language	English
Journal	Journal of Cerebral Blood Flow and Metabolism
Volume	38
Issue number	4
Pages (from-to)	659-668
ISSN	0271-678X
DOIs	https://doi.org/10.1177/0271678x17746179
Publication status	Published - 1 Apr 2018

Keywords

Journal Article

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@article{bc131da1182f44ebbeacd3c482cea123,

title = "The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [11C]Cimbi-36 labeled in two positions",

abstract = "[11C]Cimbi-36, a 5-HT2A receptor agonist PET radioligand, contains three methoxy groups amenable to [11C]-labeling. In pigs, [11C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [11C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [11C]Cimbi-36 eliminates M2 in humans, and if this changes the signal-to-background ratio. Six healthy volunteers each underwent two dynamic PET scans; after injection of [11C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [11C]Cimbi-36_5 injection. [11C]Cimbi-36_5 generated higher uptake than [11C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [11C]Cimbi-36 was 1.38 ± 0.07, whereas for [11C]Cimbi-36_5, it was 1.18 ± 0.14. This significant difference can be explained by higher non-displaceable binding caused by demethylation products in the M1 fraction such as [11C]formaldehyde and/or [11C]carbon dioxide/bicarbonate. Although often considered without any impact on binding measures, we show that small polar radiometabolites can substantially decrease the signal-to-background ratio of PET radioligands for neuroimaging. Further, we find that [11C]Cimbi-36 has a better signal-to-background ratio than [11C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT2A receptor levels in the brain.",

keywords = "Journal Article",

author = "Annette Johansen and Hansen, {Hanne D} and Claus Svarer and Szabolcs Lehel and Sebastian Leth-Petersen and Kristensen, {Jesper L} and Nic Gillings and Knudsen, {Gitte M}",

year = "2018",

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doi = "10.1177/0271678x17746179",

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TY - JOUR

T1 - The importance of small polar radiometabolites in molecular neuroimaging

T2 - A PET study with [11C]Cimbi-36 labeled in two positions

AU - Johansen, Annette

AU - Hansen, Hanne D

AU - Svarer, Claus

AU - Lehel, Szabolcs

AU - Leth-Petersen, Sebastian

AU - Kristensen, Jesper L

AU - Gillings, Nic

AU - Knudsen, Gitte M

PY - 2018/4/1

Y1 - 2018/4/1

N2 - [11C]Cimbi-36, a 5-HT2A receptor agonist PET radioligand, contains three methoxy groups amenable to [11C]-labeling. In pigs, [11C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [11C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [11C]Cimbi-36 eliminates M2 in humans, and if this changes the signal-to-background ratio. Six healthy volunteers each underwent two dynamic PET scans; after injection of [11C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [11C]Cimbi-36_5 injection. [11C]Cimbi-36_5 generated higher uptake than [11C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [11C]Cimbi-36 was 1.38 ± 0.07, whereas for [11C]Cimbi-36_5, it was 1.18 ± 0.14. This significant difference can be explained by higher non-displaceable binding caused by demethylation products in the M1 fraction such as [11C]formaldehyde and/or [11C]carbon dioxide/bicarbonate. Although often considered without any impact on binding measures, we show that small polar radiometabolites can substantially decrease the signal-to-background ratio of PET radioligands for neuroimaging. Further, we find that [11C]Cimbi-36 has a better signal-to-background ratio than [11C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT2A receptor levels in the brain.

AB - [11C]Cimbi-36, a 5-HT2A receptor agonist PET radioligand, contains three methoxy groups amenable to [11C]-labeling. In pigs, [11C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [11C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [11C]Cimbi-36 eliminates M2 in humans, and if this changes the signal-to-background ratio. Six healthy volunteers each underwent two dynamic PET scans; after injection of [11C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [11C]Cimbi-36_5 injection. [11C]Cimbi-36_5 generated higher uptake than [11C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [11C]Cimbi-36 was 1.38 ± 0.07, whereas for [11C]Cimbi-36_5, it was 1.18 ± 0.14. This significant difference can be explained by higher non-displaceable binding caused by demethylation products in the M1 fraction such as [11C]formaldehyde and/or [11C]carbon dioxide/bicarbonate. Although often considered without any impact on binding measures, we show that small polar radiometabolites can substantially decrease the signal-to-background ratio of PET radioligands for neuroimaging. Further, we find that [11C]Cimbi-36 has a better signal-to-background ratio than [11C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT2A receptor levels in the brain.

KW - Journal Article

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DO - 10.1177/0271678x17746179

M3 - Journal article

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SN - 0271-678X

VL - 38

SP - 659

EP - 668

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

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