Ovariectomy-induced depressive-like behavior and brain glucose metabolism changes in female rats are not affected by chronic mild stress.

The increased incidence of depression in women going through peri-menopause suggests that fluctuations in estrogen levels may increase the risk of developing depression. Nonetheless, this psychiatric disorder is likely to be multifactorial and consequently an additional trigger may be needed to induce depression in this population. Stress could be such a trigger. We therefore investigated the effect of ovarian estrogen depletion and chronic mild stress (CMS) on depressive-like behavior and brain metabolism in female rats. Approximately 2 and 9 weeks after estrogen depletion by ovariectomy, behavioral changes were assessed in the open-field test and the forced swim test, and brain metabolism was measured with [18F]FDG PET imaging. A subset of animals was subjected to a 6-weeks CMS protocol starting 17 days after ovariectomy. Short-term estrogen depletion had a significant effect on brain metabolism in subcortical areas, but not on behavior. Differences in depressive-like behavior were only found after prolonged estrogen depletion, leading to an increased immobility time in the forced swim test. Prolonged estrogen depletion also resulted in an increase in glucose metabolism in frontal cortical areas and hippocampus, whereas a decrease glucose metabolism was found in temporal cortical areas, hypothalamus and brainstem. Neither short-term nor prolonged estrogen depletion caused anxiety-like behavior. Changes in body weight, behavior and brain glucose metabolism were not significantly affected by CMS. In conclusion, ovarian estrogen depletion resulted in changes in brain metabolism and depressive-like behavior, but these changes were not enhanced by CMS.

N-[11C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs.

PURPOSE: Chemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[11C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[11C]methyl-AMD3465 in rats bearing a C6 tumor and assessed whether the CXCR4 occupancy by the drug Plerixafor® can be measured with this PET tracer. PROCEDURE: A subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-[11C]methyl-AMD3465 PET scans with arterial blood sampling was performed in control rats and rats pretreated with Plerixafor® (30 mg/kg, s.c). The distribution volume (V T) of the tracer was estimated by compartment modeling with a two-tissue reversible compartment model (2TRCM) and by Logan graphical analysis. The non-displaceable binding potential (BPND) was estimated with the 2TRCM. Next, CXCR4 receptor occupancy of different doses of the drug Plerixafor® (0.5-60 mg/kg) was investigated. RESULTS: The tumor could be clearly visualized by PET in control animals. Pretreatment with 30 mg/kg Plerixafor® significantly reduced tumor uptake (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). N-[11C]Methyl-AMD3465 was slowly metabolized in vivo, with 70 ± 7% of the tracer in plasma still being intact after 60 min. The tracer showed reversible in vivo binding to its receptor. Both 2TRCM modeling and Logan graphical analysis could be used to estimate V T. Pre-treatment with 30 mg/kg Plerixafor® resulted in a significant reduction in V T (2TCRM 0.87 ± 0.10 vs. 0.23 ± 0.12, p < 0.05) and BPND (1.85 ± 0.14 vs. 0.87 ± 0.12, p < 0.01). Receptor occupancy by Plerixafor® was dose-dependent with an in vivo ED50 of 12.7 ± 4.0 mg/kg. Logan analysis gave comparable results. CONCLUSION: N-[11C]Methyl-AMD3465 PET can be used to visualize CXCR4 expression and to calculate receptor occupancy. V T determined by Logan graphical analysis is a suitable parameter to assess CXCR4 receptor occupancy. This approach can easily be translated to humans and used for early drug development and optimization of drug dosing schedules.

In vivo imaging of brain androgen receptors in rats: a [(18)F]FDHT PET study.

INTRODUCTION: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16ß-[(18)F]fluoro-5α-dihydrotestosterone ([(18)F]FDHT) to image AR expression in the brain. METHODS: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [(18)F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution. RESULTS: PET imaging and ex vivo biodistribution studies showed low [(18)F]FDHT uptake in all brain regions, except pituitary. [(18)F]FDHT uptake in the surrounding cranial bones was high and increased over time. [(18)F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [(18)F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone. CONCLUSION: The results of this study indicate that imaging of AR availability in rat brain with [(18)F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of [(18)F]FDHT in rats and the poor brain penetration of the tracer likely contributed to the poor performance of [(18)F]FDHT PET in this study.