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Eur J Nucl Med Mol Imaging. 2017 Feb;44(2):308-320. doi: 10.1007/s00259-016-3544-9. Epub 2016 Nov 5.

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.

Author information

1
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. kai-chun.yang@ki.se.
2
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
3
Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark.
4
Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark.
5
Neuroscience and Pain Research Unit, Pfizer Inc., Cambridge, MA, USA.
6
Personalized Health Care and Biomarkers, AstraZeneca PET Science Center at Karolinska Institutet, Stockholm, Sweden.
7
Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.

Abstract

PURPOSE:

[11C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [11C]Lu AE92686 has high affinity for PDE10A (IC 50 = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [11C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.

METHODS:

A total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [11C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.

RESULTS:

Regional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V T) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V T values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V T values in target regions remained stable. Both pretreatment drugs significantly decreased [11C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ND) values, derived with the simplified reference tissue model (SRTM), were 13-17 in putamen and 3-5 in substantia nigra and correlated well to values from the Logan plot analysis.

CONCLUSIONS:

The method proposed for quantification of [11C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [11C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.

KEYWORDS:

MP-10; Monkey; PET; Phosphodiesterase 10A; Substantia nigra; [11C]Lu AE92686

PMID:
27817159
PMCID:
PMC5215309
DOI:
10.1007/s00259-016-3544-9
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Compliance with ethical standards Funding The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013). Conflicts of interest Author L.F. is employed part time at the AstraZeneca PET Science Center at Karolinska Institutet. Authors J.N., C.B. and B.B.A. are full time employees of H. Lundbeck A/S, and author S.G. is a full time employee of Pfizer Inc. The authors K.C.Y, V.S., N.A., S.M., A.T., C.H. and S.J.F. declare that they have no conflict of interest. Ethical approval The study was approved by the Animal Research Ethical Committee of the Northern Stockholm region (Dnr N452/11, N632/12, N633/12 and N185/14). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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