Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.
OBJECTIVE
[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 (IC50= 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 (VT) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar VTvalues could not be derived by the 2TCM. For cerebellum, a proposed reference region, VTvalues increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while VTvalues 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 (BPND) 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.
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. kai-chun.yang@ki.se.
Kai-Chun
http://orcid.org/0000-0001-8198-2509
KC
Yang
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Vladimir
V
Stepanov
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Nahid
N
Amini
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Stefan
S
Martinsson
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Akihiro
A
Takano
Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark.
Jacob
J
Nielsen
Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark.
Christoffer
C
Bundgaard
Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark.
Benny
B
Bang-Andersen
Neuroscience and Pain Research Unit, Pfizer Inc., Cambridge, MA, USA.
Sarah
S
Grimwood
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Christer
C
Halldin
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|Personalized Health Care and Biomarkers, AstraZeneca PET Science Center at Karolinska Institutet, Stockholm, Sweden.
Lars
L
Farde
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
Sjoerd J
SJ
Finnema
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D057054:Molecular Imaging / Q000379:methods*; D009928:Organ Specificity; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014230:Triazoles / Q000493:pharmacokinetics*
D008024:Ligands; C000614657:Lu AE92686; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D019275:Radiopharmaceuticals; D014230:Triazoles; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
MP-10; Monkey; PET; Phosphodiesterase 10A; Substantia nigra; [11C]Lu AE92686