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, 38 (4), 659-668

The Importance of Small Polar Radiometabolites in Molecular Neuroimaging: A PET Study With [ 11 C]Cimbi-36 Labeled in Two Positions

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The Importance of Small Polar Radiometabolites in Molecular Neuroimaging: A PET Study With [ 11 C]Cimbi-36 Labeled in Two Positions

Annette Johansen et al. J Cereb Blood Flow Metab.

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: 5-HT2A receptor; [11C]Cimbi-36; labeling position; polar radiometabolites; positron emission tomography.

Figures

Figure 1.
Figure 1.
Chemical structures and labeling position of [C]Cimbi-36 (a) and [C]Cimbi-36_5 (b). ([C]Cimbi-36_2 not shown).
Figure 2.
Figure 2.
(a) Standard uptake values (SUV) in neocortex and cerebellum (Cb) for [C]Cimbi-36 and [C]Cimbi-36_5 (points represent mean ± SD, n = 6). On the right: Maps of BPND (b and c) and corresponding SUV images (d and e) in one subject scanned with [C]Cimbi-36 (b, d) and [C]Cimbi-36_5 (c, e).
Figure 3.
Figure 3.
Radio-HPLC analysis of plasma samples 10 min after injection of [C]Cimbi-36 (a) and [C]Cimbi-36 _5 (b). Peaks: M1 – polar radiometabolites, M2 – 5′-O-glucuronide, P – parent compound. Plasma radiometabolite profiles for [C]Cimbi-36 (c) and [C]Cimbi-36_5 (d) throughout the scan (means ± SD).
Figure 4.
Figure 4.
Ratio of radioactivity concentration in plasma relative to whole blood (WB) for [C]Cimbi-36 (n = 8) and [C]Cimbi-36_5 (n = 7).
Figure 5.
Figure 5.
Proposed radiometabolism of [C]Cimbi-36 (a) and [C]Cimbi-36_5 (b).
Figure 6.
Figure 6.
Graphical representation of equation (5): ΔBPND = −1 + kM −1. Seeing as ΔVM can have a negative value, kM can be <1, resulting in an increase in BPND.

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