Sung-A Bae

Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia with PET and [18F]fallypride.

Positron emission tomography (PET) and the high affinity D2/3 radiotracer [18F]fallypride allow the assessment of D2/3 receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D2 agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR+ camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6±5.5% at 2 mg/day to 96.8±5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D2 occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.

Striatal and extrastriatal dopamine release measured with PET and [18F]fallypride

The amphetamine challenge, in which positron emission tomography (PET) or single photon emission computed tomography radioligand binding following administration of amphetamine is compared to baseline values, has been successfully used in a number of brain imaging studies as an indicator of dopaminergic function, particularly in the striatum. [18F] fallypride is the first PET radioligand that allows measurement of the effects of amphetamine on D2/D3 ligand binding in striatum and extra‐striatal brain regions in a single scanning session following amphetamine. We scanned 15 healthy volunteer subjects with [18F] fallypride at baseline and following amphetamine (0.3 mg/kg) using arterial plasma input‐based modeling as well as reference region methods. We found that amphetamine effect was robustly detected in ventral striatum, globus pallidus, and posterior putamen, and with slightly higher variability in other striatal subregions. However, the observed effect sizes in striatum were less than those observed in previous studies in our laboratory using [11C] raclopride. Robust effect was also detected in limbic extra‐striatal regions (hippocampus, amygdala) and substantia nigra, but the signal‐to‐noise ratio was too low to allow accurate measurement in cortical regions. We conclude that [18F] fallypride is a suitable ligand for measuring amphetamine effect in striatum and limbic regions, but it is not suitable for measuring the effect in cortical regions and may not provide the most powerful way to measure the effect in striatum. Synapse 64:350–362, 2010.

A positron emission tomography radioligand for the in vivo labeling of metabotropic glutamate 1 receptor: (3-ethyl-2-[11C]methyl-6-quinolinyl)(cis- 4-methoxycyclohexyl)methanone.

A selective metabotropic glutamate 1 receptor (mGlu1) antagonist was labeled with the positron-emitting radioisotope carbon-11 and evaluated in ex vivo biodistribution studies and micro-positron emission tomography (micro-PET) imaging experiments in rats. Results from animal experiments demonstrate that the radioligand [11C]2 is the first PET tracer capable of labeling the rat mGlu1 receptor in vivo.

Reproducibility and sensitivity to pharmacological challenge of [11C]-ABP688 in non-human primate brain

Purpose: 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-C-methyl-oxime ([C]-ABP688) is a highly-selective antagonist PET tracer for imaging the metabotropic glutamate receptor subtype 5 (mGluR5). The aims of this study were to test the reproducibility of outcome measures using this tracer with anesthetized baboons and to test the effect of challenge with the glutamate releaser N-acetylcysteine (NAC) on [C]-ABP688 specific binding.