Characterization of an intraperitoneal ovarian cancer xenograft model in nude rats using noninvasive microPET imaging.

MicroPET is a noninvasive imaging modality that can potentially track tumor development in nude rats using the radiotracer fluorine 18-fluorodeoxyglucose ((18)F-FDG). Our goal was to determine whether microPET, as opposed to more invasive techniques, could be used to noninvasively monitor the development of ovarian cancer in the peritoneal cavity of nude rats for monitoring treatment response in future studies. Female nude rats were inoculated intraperitoneally with 36 million NIH:OVCAR-3 cells. Imaging was carried out at 2, 4, 6, or 8 weeks postinoculation. Each rat was fasted overnight and intravenously injected with 11.1 MBq (300 microCi) of (18)F-FDG in 0.2 mL of saline. Thirty minutes following injection, the rats were placed in the microPET and scanned for 30 min. After imaging, rats were euthanized for ascites and tissue collection for biodistribution and histopathologic correlation. Standard uptake values (SUVs) of (18)F-FDG within the peritoneal cavity were also calculated from regions of interest analysis of the microPET images. MicroPET images showed diffuse increased uptake of (18)F-FDG throughout the peritoneal cavity of tumor rats (mean SUV=4.64) compared with control rats (mean SUV=1.03). Ascites gathered from tumor-bearing rats had increased (18)F-FDG uptake as opposed to the peritoneal fluid collected from control rats. Biodistribution data revealed that the percent injected dose per gram (% ID/g) was significantly higher in tumor-bearing rats (6.29%) than in control rats (0.59%) in the peritoneal lymph nodes. Pathology verified that these lymph nodes were more reactive in tumor-bearing rats. By 6 weeks, some rats developed solid masses within the peritoneum, which could be detected on microPET images and confirmed as tumor by histopathology. (18)F-FDG uptake in these tumors at necropsy was 2.83% ID/g. These results correlate with previous invasive laparoscopic studies of the same tumor model and demonstrate that microPET using (18)F-FDG is a promising noninvasive tool to localize and follow tumor growth in an intraperitoneal ovarian cancer model.

Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response.

BACKGROUND: Treatment of major depression with antidepressants is generally associated with a delay in onset of clinical response. Functional brain correlates of this phenomenon have not been previously characterized. METHODS: Time course of changes in brain glucose metabolism were measured using positron emission tomography in hospitalized unipolar depressed patients treated with fluoxetine. Time-specific and response-specific effects were examined at 1 and 6 weeks of treatment. RESULTS: Changes were seen over time, and characterized by three distinct patterns: 1) common changes at 1 and 6 weeks, 2) reversal of the 1-week pattern at 6 weeks, and 3) unique changes seen only after chronic treatment. Fluoxetine responders and nonresponders, similar at 1 week, were differentiated by their 6-week pattern. Clinical improvement was uniquely associated with limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, parietal, anterior, and posterior cingulate). Failed response was associated with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal changes. CONCLUSIONS: Chronic treatment and clinical response to fluoxetine was associated with a reciprocal pattern of subcortical and limbic decreases and cortical increases. Reversal in the week-1 pattern at 6 weeks suggests a process of adaptation in specific brain regions over time in response to sustained serotonin reuptake inhibition. The inverse patterns in responders and nonresponders also suggests that failure to induce these adaptive changes may underlie treatment nonresponse.

Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness.

OBJECTIVE: Theories of human behavior from Plato to Freud have repeatedly emphasized links between emotion and reason, a relationship now commonly attributed to pathways connecting phylogenetically "old" and "new" brain regions. Expanding on this theory, this study examined functional interactions between specific limbic and neocortical regions accompanying normal and disease-associated shifts in negative mood state. METHOD: Regions of concordant functional change accompanying provocation of transient sadness in healthy volunteers and resolution of chronic dysphoric symptoms in depressed patients were examined with two positron emission tomography techniques: [15O]water and [18F]fluorodeoxyglucose, respectively. RESULTS: With sadness, increases in limbic-paralimbic blood flow (subgenual cingulate, anterior insula) and decreases in neocortical regions (right dorsolateral prefrontal, inferior parietal) were identified. With recovery from depression, the reverse pattern, involving the same regions, was seen--limbic metabolic decreases and neocortical increases. A significant inverse correlation between subgenual cingulate and right dorsolateral prefrontal activity was also demonstrated in both conditions. CONCLUSIONS: Reciprocal changes involving subgenual cingulate and right prefrontal cortex occur with both transient and chronic changes in negative mood. The presence and maintenance of functional reciprocity between these regions with shifts in mood in either direction suggests that these regional interactions are obligatory and probably mediate the well-recognized relationships between mood and attention seen in both normal and pathological conditions. The bidirectional nature of this limbic-cortical reciprocity provides additional evidence of potential mechanisms mediating cognitive ("top-down"), pharmacological (mixed), and surgical ("bottom-up") treatments of mood disorders such as depression.

Effect of partition coefficient, permeability surface product, and radioisotope on the signal-to-noise ratio in PET functional brain mapping: a computer simulation.

In this work we use a computer simulation to estimate the magnitude of improvement in the signal-to-noise ratio of PET functional brain mapping studies as a function of partition coefficient and permeability surface product for O-14, F-17, and O-15 labeled flow tracers. A model for signal-to-noise ratio is derived from the Kety model for inert diffusible blood flow tracers. The results of the simulation suggest that moderate increases in partition coefficient and permeability surface product compared with water would lead to an increase in signal-to-noise ratio of a factor of about 3.

Xenon effects on regional cerebral blood flow assessed by 15O-H2O positron emission tomography: implications for hyperpolarized xenon MRI.

Subjective and physiologic effects of 33% inhaled Xe were measured with 15O-water positron emission tomography (PET) in 3 subjects at rest and during visual stimulation. The procedure was well tolerated. Robust functional activations of the visual cortex were obtained after xenon (Xe) inhalation as well as air breathing. However, Xe inhalation was followed by smaller size, but significant decreases of regional cerebral blood flow (rCBF) in visual cortex relative to the air-breathing baseline, both during visual stimulation and at rest. No such decreases were found in other sensory or motor regions.

Use of oxygen-15 to measure oxygen-carrying capacity of blood substitutes in vivo.

A method for determining oxygen-carrying capacity of blood substitutes has been developed using the short-lived cyclotron-produced positron-emitting isotope 15O. This method measures the oxygen-carrying capacity of the blood substitutes in vivo in the presence of red blood cells and allows determination of changes in the oxygen-carrying capacity over time after exchange transfusion. This method is applied to the blood substitutes of liposome-encapsulated hemoglobin (LEH) and cell-free hemoglobin (Hb). We have used 15O (half-life of 2 min) to quantitate the lung uptake and tissue delivery of [15O2]LEH. Lung uptake studies were performed in intubated, catheterized rats after a 40% exchange transfusion of bovine LEH (LEBH; 0.68 g Hb/kg body wt), human hemolysate LEH (LEHH; 1.0 g Hb/kg body wt), or free bovine hemoglobin (SFHS; 0.56 g Hb/kg body wt). A bolus inhalation of 15O2 (3-5 mCi) was given at 15 min, 3 h, and 24 h post-transfusion. Arterial blood samples were collected, spun, and separated into LEH, red blood cell, and plasma fractions. 15O activity and hemoglobin content were determined for each fraction. Oxygen-carrying capacity was calculated as a percentage of the original red blood cell fraction removed. For LEBH, the carrying capacity was 15% at 15 min, 13% at 3 h, and 1% at 24 h. For LEHH, the carrying capacity was 30% at 15 min, 26% at 3 h, and 19% at 24 h. The marked decrease in carrying capacity at 24 h for LEBH compared with LEHH was attributable to the increased formation of methemoglobin in the circulating LEBH rather than increased removal from circulation, because total hemoglobin concentrations measured for both LEH samples decreased at a similar rate during the 24 h. The presence of methemoglobin reductase and other naturally occurring antioxidants in the LEHH may be responsible for maintaining the higher levels of oxyhemoglobin. Oxygen-carrying capacity for SFHS also decreased over time but at a much sharper rate compared with both LEH formulations. The carrying capacity for SFHS of 8% measured at 15 min decreased to 0.3% at 3 h and undetectable levels at 24 h. This sharper decrease in carrying capacity for SFHS is attributable to the rapid removal of the hemoglobin from circulation.

Cingulate function in depression: a potential predictor of treatment response.

The relationship between pretreatment regional cerebral glucose metabolism and eventual antidepressant drug response was measured using positron emission tomography (PET) in hospitalized patients with unipolar depression. Rostral anterior cingulate metabolism uniquely differentiated eventual treatment responders from non-responders. Hypometabolism characterized non-responders when compared with controls, in contrast to responders who were hypermetabolic. Metabolism in no other region discriminated the two groups, nor did associated demographic, clinical or behavioral measures, including motor speed, cognitive performance, depression severity or illness chronicity. Cingulate hypermetabolism may represent an important adaptive response to depression and failure of this response may underlie poor outcome. A critical role for rostral cingulate area 24a/b in the limbic-cortical network involved in abnormal mood states is proposed.

Use of implicit motor imagery for visual shape discrimination as revealed by PET.

Positron emission tomography (PET) can be used to map brain regions that are active when a visual object (for example, a hand) is discriminated from its mirror form. Chronometric studies suggest that viewers 'solve' this visual shape task by mentally modelling it as a reaching task, implicitly moving their left hand into the orientation of any left-hand stimulus (and conversely for a right-hand stimulus). Here we describe an experiment in which visual and somatic processing are dissociated by presenting right hands to the left visual field and vice versa. Frontal (motor), parietal (somatosensory) and cerebellar (sensorimotor) regions similar to those activated by actual and imagined movement are strongly activated, whereas primary somatosensory and motor cortices are not. We conclude that mental imagery is realized at intermediate-to-high order, modality-specific cortical systems, but does not require primary cortex and is not constrained to the perceptual systems of the presented stimuli.

Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics.

We scanned 18 patients with schizophrenia who had never received neuroleptic medication and 20 age- and sex-matched controls by positron emission tomography with 18-F-fluorodeoxyglucose (fludeoxyglucose F 18) as a tracer of glucose metabolism. Subjects performed the Continuous Performance Test during 18-F-fluorodeoxyglucose uptake. Scan results were converted to metabolic rates, and computer algorithms were used to identify cortical regions. Previous reports of relative hypofrontality in schizophrenia were confirmed, indicating that this finding is not an artifact of previous treatment. Significantly reduced ratios of inferior and medial frontal regions to occipital cortex were found, together with diminished metabolism in the basal ganglia. This suggests the presence of a combined frontostriatal dysfunction in schizophrenia.

Radiolabeled hypoxic cell sensitizers: tracers for assessment of ischemia.

Hypoxic, non-functional, but viable, tissue may exist in heart and brain following an arterial occlusion. Identification of such tissue in vivo is crucial to the development of effective treatment strategies. It has been suggested that certain compounds capable of sensitizing hypoxic tumor cells to killing by x-rays (i.e., misonidazole) might serve as in vivo markers of hypoxic tissue in ischemic myocardium or brain if properly radiolabeled. To this end we have radiolabeled two fluorinated analogs of nitroimidazole based hypoxic cell sensitizers with the 110 minute half-lived positron-emitting fluorine-18. The ability of these tracers to quantitate the presence of hypoxic tissue has been studied in a gerbil stroke model. The in vivo uptake of one of these tracers [F-18]-fluoronormethyoxymisonidazole is dependent on the extent of tissue hypoxia, and thus, appears to have potential as a diagnostic indicator of non-functional but viable tissue when the tracer is used in conjunction with positron emission tomography.

Synthesis and biodistribution of 18F-labeled fluoronitroimidazoles: potential in vivo markers of hypoxic tissue.

Three 18F labeled fluoronitroimidazoles have been prepared as potential in vivo markers of hypoxic cells in tumors, and ischemic areas of the heart and brain. 1-(2-Nitroimidazolyl)-3-[18F]fluoro-2-hydroxypropanol (18F]fluoro-normethoxymisonidazole) 4, 1-(2-[18F]fluoroethyl)-2-nitroimidazole 7, and 1-(2-[18F]-fluoroethyl)-2-methyl-5-nitroimidazole ([18F]fluoro-norhydroxymetronidazole) 10 were prepared in average radiochemical yields of less than 1%, 23% and 15-43% (8% at the no carrier-added level) respectively at end-of-synthesis. The in vivo biodistribution in rats was determined for each of the 18F labeled fluoronitroimidazoles. At 1 and 3 h after administration, the tissue distribution of each of the 18F labeled nitroimidzaoles was quite uniform and consistent with that of nitroimidazoles previously studied. These results suggest the need for a suitable animal model to evaluate their potential as in vivo markers of hypoxic tissue in the brain.

2-[18F]fluoroputrescine: preparation, biodistribution, and mechanism of defluorination.

A new radiolabeled analog of putrescine, 18F labeled 2-fluoroputrescine, has been prepared as a potential in vivo imaging agent for prostate and prostate derived tumors. The radiosynthesis yielded 1.5-4.5 mCi amounts of the 18F labeled putrescine analog (1-3% yields at end-of-synthesis), with specific activities ranging from 0.85-4.3 Ci/mmol, in a synthesis time of 2 h. The in vivo biodistribution in mature male rats showed considerable uptake by the bone, indicating defluorination of the compound. In animals pretreated with aminoguanidine, an inhibitor of diamine oxidase, the enzyme important in the metabolism of putrescine, defluorination was markedly reduced, but uptake by the prostate did not improve. These results suggest the need for development of a 18F labeled analog of putrescine which does not defluorinate in vivo, and which has biological properties similar to putrescine.

Synthesis and uptake of no-carrier-added 1-[11C]putrescine into rat prostate.

No carrier-added 1-[11C]putrescine has been prepared using a simple two-step procedure. Radiochemical yields of 1-2% at end-of-synthesis were obtained in a synthesis time of 50-60 min. The in vivo uptake of no carrier-added 1-[11C]putrescine into rat prostate was determined and compared to the uptake of no carrier-added material containing varying amounts of non-radioactive putrescine. The in vivo results indicate that the mechanism of uptake into the prostate is saturable.