The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [11C]Cimbi-36 labeled in two positions
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The importance of small polar radiometabolites in molecular neuroimaging : A PET study with [11C]Cimbi-36 labeled in two positions. / Johansen, Annette; Hansen, Hanne D; Svarer, Claus; Lehel, Szabolcs; Leth-Petersen, Sebastian; Kristensen, Jesper L; Gillings, Nic; Knudsen, Gitte M.
In: Journal of Cerebral Blood Flow and Metabolism, Vol. 38, No. 4, 04.2018, p. 659-668.Research output: Contribution to journal › Journal article › Research › peer-review
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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
Y1 - 2018/4
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
U2 - 10.1177/0271678X17746179
DO - 10.1177/0271678X17746179
M3 - Journal article
C2 - 29215308
VL - 38
SP - 659
EP - 668
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 4
ER -
ID: 186634623