Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D-2 and Histamine H-3 Receptors:A PET Study in Healthy Rats

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D-2/D-3 agonist/H-3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods: Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D-2/D-3 receptor ligand [C-11]raclopride or the histamine H-3 receptor ligand [C-11]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [C-11]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [C-11]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution (V-T) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results: Dopamine D-2/3 receptor occupancies in the striatum were 22.6 +/- 18.0 and 84.0 +/- 3.5% (mean +/- SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the V-T values of [C-11]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H-3 receptor occupancies were 11.9 +/- 8.5 and 40.3 +/- 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions: Target engagement of AG-0029 as an agonist at dopamine D-2/D-3 receptors and an antagonist at histamine H-3 receptors could be demonstrated in the rat brain with [C-11]raclopride and [C-11]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D-2/D-3 and moderate (submicromolar) affinity to H-3 receptors

Molecular imaging with positron emission tomography and computed tomography (PET/CT) for selecting first-line targeted treatment in metastatic breast cancer: a cost-effectiveness study

Our aim was to evaluate the potential cost-effectiveness of PET/CT with FES and 89Zr-trastuzumab compared to pathology to select first-line targeted treatment in metastatic breast cancer (MBC) patients with non-rapidly progressive disease. A previously published and validated model was extended and adapted for this analysis. Two alternative scenarios were compared. In the care as usual pathway first-line targeted treatment of MBC patients was assigned on the basis of pathology results, while in the intervention pathway treatment selection was based on the results from the PET/CT imaging. Costs, life years gained (LYG) and incremental cost-effectiveness ratios (ICER) were calculated. More MBC lesions were detected in the intervention pathway than in the care as usual pathway. The diagnostic costs to evaluate the receptor status and the treatment costs were higher in the intervention strategy, as were total costs and total LYG. The ICER for replacing biopsies with PET/CT imaging with FES and 89Zr-trastuzumab, assuming sensitivity of 77.1% and specificity of 80%, ranged from €71,000 to €77,000 per LYG. When assuming sensitivity of 80% and specificity of 76.7%, the ICER for replacing biopsies with PET/CT imaging with FES and 89Zr-trastuzumab ranged from to €74,000 to €80,000 per LYG. The application of PET/CT with FES and 89Zr-trastuzumab in first-line treatment selection for MBC patients has the potential to be a cost-effective intervention. Our analysis demonstrated that even a small increase in the sensitivity and the specificity of PET/CT can have a large impact on its potential cost-effectiveness

PET and SPECT of Neurobiological Systems

XVIII, 818 p. 282 illus., 108 illus. in color.onl