Impact of image-based motion correction on dopamine D3/D2 receptor occupancy-comparison of groupwise and frame-by-frame registration approaches

© 2015, Jiao et al.Background: Image registration algorithms are frequently used to align the reconstructed brain PET frames to remove subject head motion. However, in occupancy studies, this is a challenging task where competitive binding of a drug can further reduce the available signal for registration. The purpose of this study is to evaluate two kinds of algorithms—a conventional frame-by-frame (FBF) registration and a recently introduced groupwise image registration (GIR), for motion correction of a dopamine D3/D2 receptor occupancy study. Methods: The FBF method co-registers all the PET frames to a common reference based on normalised mutual information as the spatial similarity. The GIR method incorporates a pharmacokinetic model and conducts motion correction by maximising a likelihood function iteratively on tracer kinetics and subject motion. Data from eight healthy volunteers scanned with [11C]-(+)-PHNO pre- and post-administration of a range of doses of the D3 antagonist GSK618334 were used to compare the motion correction performance. Results: The groupwise registration achieved improved motion correction results, both by visual inspection of the dynamic PET data and by the reduction of the variability in the outcome measures, and required no additional steps to exclude unsuccessfully realigned PET data for occupancy modelling as compared to frame-by-frame registration. Furthermore, for the groupwise method, the resultant binding potential estimates had reduced variation and bias for individual scans and improved half maximal effective concentration (EC50) estimates were obtained for the study as a whole. Conclusions: These results indicate that the groupwise registration approach can provide improved motion correction of dynamic brain PET data as compared to frame-by-frame registration approaches for receptor occupancy studies

Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia : analysis of the CATIE data

Background Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics. Methods The dataset from 481 subjects (risperidone, N = 172, olanzapine, N = 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated. Results The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68–70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). Conclusion The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65–80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia.peer-reviewe

Kinetic models for estimating occupancy from single-scan PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.</p

Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D2 dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5–8, followed by 300 mg/d quetiapine IR on days 9–12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D2 receptor occupancy was calculated using the simplified reference tissue model. Peak D2 receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50±4% and 32±11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D2 receptor occupancy was similarly low for both formulations (IR 7±7%, XR 8±6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D2 receptor occupancy than typical antipsychotics