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Purpose: Ovarian cancer (OC) leads to poor survival rates mainly due to late stage detection and innate or acquired resistance to chemotherapy. Thus, efforts have been made to exploit the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) to treat OC. However, patients eventually become resistant to these treatments as well. HER2 overexpression contributes to the acquired resistance to ER-targeted treatment. Trastuzumab treatment, on the other hand, can result in increased expression of ER, which, in turn, increases the sensitivity of the tumors towards anti-estrogen therapy. More insight into the crosstalk between ER and HER2 signaling could improve our knowledge about acquired resistance in ovarian cancer. The aim of this study was to evaluate whether PET could be used to detect changes in ER expression induced by HER2-targeted treatment in vivo., Procedures: Male athymic nude mice were subcutaneously (sc) inoculated with 10 6 SKOV3 human ovarian cancer cells (HER2+/ER+). Two weeks after inoculation, tumor-bearing mice were treated intraperitoneally with either vehicle, the HER2 antibody trastuzumab (20 mg/kg, 2×/week), or the HER2-tyrosine kinase inhibitor lapatinib (40 mg/kg, 5 days/week) for 2 weeks. Thereafter, ER expression in the tumor was assessed by PET imaging with 16α-[ 18 F]-fluoro-17β-estradiol ([ 18 F]FES). Tumors were excised for ex vivo ER and HER2 measurement with Western blotting and immunohistochemistry., Results: All treatments led to smaller tumors than vehicle-treated tumors. Higher [ 18 F]FES maximum standardize tumor uptake (SUV max ) was observed in animals treated with trastuzumab (+ 29 %, P = 0.002) or lapatinib (+ 20 %, P = 0.096) than in vehicle-treated controls. PET results were in agreement with ex vivo analyses., Conclusion: FES-PET imaging can detect changes in ER expression induced by HER2-targeted treatment and therefore can be used to investigate the crosstalk between ER and HER2 in a noninvasive manner.

Purpose: [ 18 F]Fluoroethoxybenzovesamicol ([ 18 F]FEOBV) is a radioligand for the vesicular acetylcholine transporter (VAChT), a marker of the cholinergic system. We evaluated the quantification of [ 18 F]FEOBV in rats in control conditions and after partial saturation of VAChT using plasma and reference tissue input models and test-retest reliability., Procedure: Ninety-minute dynamic [ 18 F]FEOBV PET scans with arterial blood sampling were performed in control rats and rats pretreated with 10 μg/kg FEOBV. Kinetic analyses were performed using one- (1TCM) and two-tissue compartmental models (2TCM), Logan and Patlak graphical analyses with metabolite-corrected plasma input, reference tissue Patlak with cerebellum as reference tissue, standard uptake value (SUV) and SUV ratio (SUVR) using 60- or 90-min acquisition. To assess test-retest reliability, two dynamic [ 18 F]FEOBV scans were performed 1 week apart., Results: The 1TCM did not fit the data. Time-activity curves were more reliably estimated by the irreversible than the reversible 2TCM for 60 and 90 min as the influx rate K i showed a lower coefficient of variation (COV, 14-24 %) than the volume of distribution V T (16-108 %). Patlak graphical analysis showed a good fit to the data for both acquisition times with a COV (12-27 %) comparable to the irreversible 2TCM. For 60 min, Logan analysis performed comparably to both irreversible models (COV 14-32 %) but showed lower sensitivity to VAChT saturation. Partial saturation of VAChT did not affect model selection when using plasma input. However, poor correlations were found between irreversible 2TCM and SUV and SUVR in partially saturated VAChT states. Test-retest reliability and intraclass correlation for SUV were good., Conclusion: [ 18 F]FEOBV is best modeled using the irreversible 2TCM or Patlak graphical analysis. SUV should only be used if blood sampling is not possible.

Purpose: An important issue in rodent imaging is the question whether a mixed population of male and female animals can be used rather than animals of a single sex. For this reason, the present study examined the test-retest stability of positron emission tomography (PET) with 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) in male rats and female rats at different phases of the estrous cycle., Procedures: Long-Evans rats (age 1 year) were divided into three groups: (1) males (n = 6), (2) females in metestrous (low estrogen levels, n = 9), and (3) females in proestrous (high estrogen levels, n = 7). Two standard [ 18 F]FDG scans with rapid arterial blood sampling were made at an interval of 10 days in subjects anesthetized with isoflurane and oxygen. Body temperature, heart rate, and blood oxygenation were continuously monitored. Regional cerebral metabolic rates of glucose were calculated using a Patlak plot with plasma radioactivity as input function., Results: Regional metabolic rate of glucose (rCMR glucose ) in male and female rats, or [ 18 F]FDG uptake in females at proestrous and metestrous, was not significantly different, but females showed significantly higher standardized uptake values (SUVs) and Patlak flux than males, particularly in the initial scan. The relative difference between the scans and the test-retest variability (TRV) were greater in females than in males. Intra-class correlation coefficients (ICCs) of rCMR glucose , SUV, normalized SUV, and glucose flux were good to excellent in males but poor to moderate in females., Conclusions: Based on these data for [ 18 F]FDG, the mixing of sexes in imaging studies of the rodent brain will result in an impaired test-retest stability of PET data and a need for larger group sizes to maintain statistical power in group comparisons. The observed differences between males and females do not indicate any specific gender difference in cerebral metabolism but are related to different levels of non-radioactive glucose in blood plasma during isoflurane anesthesia.