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S R Cherry

Publications and source records attributed to S R Cherry.

At least 37 records · Page 2Linked to original sources
PubMed2000

Synthesis of 8-[(18)F]fluoroguanine derivatives: in vivo probes for imaging gene expression with positron emission tomography.

A new method for the preparation of 8-[(18)F]fluoroguanine derivatives based on a direct radiofluorination reaction has been developed. The radiofluorination of ganciclovir (1a) with [(18)F]F(2) was carried out in absolute ethanol in the presence of tetraethylammonium hydroxide at room temperature to give 8-[(18)F]fluoroganciclovir (3a) in an approximately 1% radiochemical yield. Similarly, 8-[(18)F]fluoropenciclovir (3b), 8-[(18)F]fluoroacyclovir (3c), and 8-[(18)F]fluoroguanosine (3d) were synthesized from penciclovir (1b), acyclovir (1c), and guanosine (1d), respectively, using [(18)F]F(2). The structural analyses of the final products (3a, 3b, 3c, and 3d) were carried out after (18)F decay by (1)H, (13)C, and (19)F nuclear magnetic resonance and high resolution mass spectroscopy.

Acyclovir↗
PubMed2000

In vivo imaging of neuronal activation and plasticity in the rat brain by high resolution positron emission tomography (microPET).

The study of neural repair and neuroplasticity in rodents would be enhanced by the ability to assess neuronal function in vivo. Positron emission tomography (PET) is used to study brain plasticity in humans, but the limited resolution and sensitivity of conventional scanners have generally precluded the use of PET to study neuroplasticity in rodents. We now demonstrate that microPET, a PET scanner developed for use with small animals, can be used to assess metabolic activity in different regions of the conscious rodent brain using [18F]fluorodeoxyglucose (FDG) as the tracer, and to monitor changes in neuronal activity. Limbic seizures result in dramatically elevated metabolic activity in the hippocampus, whereas vibrissal stimulation results in more modest increases in FDG uptake in the contralateral neocortex. We also show that microPET can be used to study lesion-induced plasticity of the brain. Cerebral hemidecortication resulted in diminished relative glucose metabolism in the neostriatum and thalamus ipsilateral to the lesion, with subsequent, significant recovery of metabolic function. These studies demonstrate that microPET can be used for serial assessment of metabolic function of individual, awake rats with a minimal degree of invasiveness, and therefore, has the potential for use in the study of brain disorders and repair.

Age Factors↗
PubMed2000

Quantitative assessment of longitudinal metabolic changes in vivo after traumatic brain injury in the adult rat using FDG-microPET.

With the advent and emerging importance of neurobiology and its relation to behavior, scientists desire the capability to apply noninvasive, quantitative imaging of neuronal activity to small rodents. To this end, the authors' laboratory has developed microPET, a high-resolution positron emission tomography (PET) scanner that is capable of performing in vivo molecular imaging at a resolution sufficient to resolve major structures in the rat brain. The authors report in this article that, in conjunction with 2-[18F]fluoro-2-deoxyglucose (FDG), microPET provides accurate rates of cerebral glucose metabolism (59.7 to 108.5 micromol/100 g x min) in conscious adult rats as validated by within-subject autoradiographic measurements (59.5 to 136.2 micromol/100 g x min; r = 0.88; F[1,46] = 168.0; P < 0.001). By conducting repeated quantitative scanning, the authors demonstrate the sensitivity and accuracy of FDG-microPET to detect within-subject metabolic changes induced by traumatic brain injury. In addition, the authors report that longitudinal recovery from traumatic brain injury-induced metabolic depression, as measured by quantitative FDG-microPET, is significantly correlated (r = 0.65; P < 0.05) to recovery of behavioral dysfunction, as assessed by the Morris Water Maze performance of the same rats, after injury. This is the first study to demonstrate that FDG-microPET is quantitative, reproducible, and sensitive to metabolic changes, introducing a new approach to the longitudinal study of small animal models in neuroscience research.

Animals↗
PubMed2000

Comparison of 3-D maximum a posteriori and filtered backprojection algorithms for high-resolution animal imaging with microPET.

We have evaluated the performance of two three-dimensional (3-D) reconstruction algorithms with data acquired from microPET, a high resolution tomograph dedicated to small animal imaging. The first was a linear filtered-backprojection algorithm (FBP) with reprojection of the missing data, and the second was a statistical maximum a posteriori probability algorithm (MAP). The two algorithms were evaluated in terms of their resolution performance, both in phantoms and in vivo. Sixty independent realizations of a phantom simulating the brain of a baby monkey were acquired, each containing three million counts. Each of these realizations was reconstructed independently with both algorithms. The ensemble of the 60 reconstructed realizations was used to estimate the standard deviation as a measure of the noise for each reconstruction algorithm. More detail was recovered in the MAP reconstruction without an increase in noise relative to FBP. Studies in a simple cylindrical compartment phantom demonstrated improved recovery of known activity ratios with MAP. Finally, in vivo studies also demonstrated a clear improvement in spatial resolution using the MAP algorithm. The quantitative accuracy of the MAP reconstruction was also evaluated by comparison with autoradiography and direct well counting of tissue samples and was shown to be superior.

Algorithms↗
PubMed2000

Design and evaluation of an LSO PET detector for breast cancer imaging.

Functional imaging with positron emission tomography (PET) may be a promising technique in conjunction with x-ray mammography for breast cancer patient management. Conventional whole body PET scanners provide metabolic images of breast cancer patients with several shortcomings related to the general-purpose nature of these systems. In whole body scanners, the detectors are typically 20-30 cm away from the breast or axilla, reducing sensitivity, and these scanners have relatively large detector elements (> 4 mm), limiting spatial resolution. Dedicated PET systems for breast imaging aim to overcome these limitations and improve the overall diagnostic quality of the images by bringing the detectors closer to the area to be imaged, thereby improving sensitivity, and by using smaller detector elements to improve the spatial resolution. We have designed and developed a modular PET detector that is composed of a 9x9 array of 3x3x20 mm3 lutetium oxyorthosilicate (LSO) scintillator crystals coupled to an optical fiber taper, which in turn is coupled to a Hamamatsu R5900-C8 position-sensitive photomultiplier tube. These detectors can be tiled together without gaps to construct large area detector arrays to form a dedicated PET breast cancer imaging system. Two complete detector modules have been built and tested. All detector elements are clearly visualized upon flood irradiation of the module. The intrinsic spatial resolution (full-width at half-maximum) was measured to be 2.26 mm (range 1.8-2.6 mm). The average energy resolution was 19.5% (range 17%-24%) at 511 keV. The coincidence time resolution was measured to be 2.4 ns. The detector efficiency for 511 keV gamma rays was 53% using a 350 keV energy threshold. These promising results support the feasibility of developing a high resolution, high sensitivity dedicated PET scanner for breast cancer applications.

Breast Neoplasms↗
PubMed2000

Retroviral expression in embryonic stem cells and hematopoietic stem cells.

Achieving long-term retroviral expression in primary cells has been problematic. De novo DNA methylation of infecting proviruses has been proposed as a major cause of this transcriptional repression. Here we report the development of a mouse stem cell virus (MSCV) long terminal repeat-based retroviral vector that is expressed in both embryonic stem (ES) cells and hematopoietic stem (HS) cells. Infected HS cells and their differentiated descendants maintained long-term and stable retroviral expression after serial adoptive transfers. In addition, retrovirally infected ES cells showed detectable expression level of the green fluorescent protein (GFP). Moreover, GFP expression of integrated proviruses was maintained after in vitro differentiation of infected ES cells. Long-term passage of infected ES cells resulted in methylation-mediated silencing, while short-term expression was methylation independent. Tissues of transgenic animals, which we derived from ES cells carrying the MSCV-based provirus, did not express GFP. However, treatment with the demethylating agent 5-azadeoxycytidine reactivated the silent provirus, demonstrating that DNA methylation is involved in the maintenance of retroviral repression. Our results indicate that retroviral expression in ES cells is repressed by methylation-dependent as well as methylation-independent mechanisms.

Adoptive Transfer↗
PubMed1999

Chromatin remodeling directly activates V(D)J recombination.

V(D)J recombination substrate choice is regulated to ensure that the appropriate gene segments are rearranged during lymphocyte development. It has been proposed that regulation of substrate usage is determined by changes in accessibility of the DNA targets. We show that Rag-mediated recombination of an episomal substrate in cells is affected by its packaging into chromatin. Chromatinized substrates were inefficiently rearranged, and methylation further reduced recombination. Disruption of nucleosomes by using butyrate on methylated substrates was sufficient to activate recombination, and dexamethasone could activate recombination in the absence of detectable transcription. Therefore, chromatin structure, and its manipulation by altering nucleosome positioning, can directly affect recombination efficiencies.

Animals↗
PubMed1999

Application of positron emission tomography to determine cerebral glucose utilization in conscious infant monkeys.

Cerebral glucose metabolism has been used as a marker of cerebral maturation and neuroplasticity. In studies addressing these issues in young non-human primates, investigators have used positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose (FDG) to calculate local cerebral metabolic rates of glucose (1CMRG1c). Unfortunately, these values were influenced by anesthesia. In order to avoid this confounding factor, we have established a method that permits reliable measurements in young conscious vervet monkeys using FDG-PET. Immature animals remained in a conscious, resting state during the initial 42 min of FDG uptake as they were allowed to cling to their anesthetized mothers. After FDG uptake, animals were anesthetized and placed in the PET scanner with data acquisition beginning at 60 min post-FDG injection. FDG image sets consisted of 30 planes separated by 1.69 mm, parameters sufficient to image the entire monkey brain. Our method of region-of-interest (ROI) analysis was assessed within and between raters and demonstrated high reliability (P < 0.001). To illustrate that our method was sensitive to developmental changes in cerebral glucose metabolism, quantitative studies of young conscious monkeys revealed that infant monkeys 6-8 months of age exhibited significantly higher 1CMRG1c values (P < 0.05) in all regions examined, except sensorimotor cortex and thalamus, compared to monkeys younger than 4 months of age. This method provided high resolution images and 1CMRG1c values that were reliable within age group. These results support the application of FDG-PET to investigate questions related to cerebral glucose metabolism in young conscious non-human primates.

Age Factors↗
PubMed1999

Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography.

We are developing quantitative assays to repeatedly and noninvasively image expression of reporter genes in living animals, using positron emission tomography (PET). We synthesized positron-emitting 8-[18F]fluoroganciclovir (FGCV) and demonstrated that this compound is a substrate for the herpes simplex virus 1 thymidine kinase enzyme (HSV1-TK). Using positron-emitting FGCV as a PET reporter probe, we imaged adenovirus-directed hepatic expression of the HSV1-tk reporter gene in living mice. There is a significant positive correlation between the percent injected dose of FGCV retained per gram of liver and the levels of hepatic HSV1-tk reporter gene expression (r2 > 0.80). Over a similar range of HSV1-tk expression in vivo, the percent injected dose retained per gram of liver was 0-23% for ganciclovir and 0-3% for FGCV. Repeated, noninvasive, and quantitative imaging of PET reporter gene expression should be a valuable tool for studies of human gene therapy, of organ/cell transplantation, and of both environmental and behavioral modulation of gene expression in transgenic mice.

Animals↗
PubMed1999

Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals.

Reporter genes (e.g. beta-galactosidase, chloramphenicol-acetyltransferase, green fluorescent protein, luciferase) play critical roles in investigating mechanisms of gene expression in transgenic animals and in developing gene delivery systems for gene therapy. However, measuring expression of these reporter genes requires biopsy or death. We now report a procedure to image reporter gene expression repetitively and non-invasively in living animals with positron emission tomography (PET), using the dopamine type 2 receptor (D2R) as a reporter gene and 3-(2'-[18F]fluoroethyl)spiperone (FESP) as a reporter probe. We use a viral delivery system to demonstrate the ability of this PET reporter gene/PET reporter probe system to image reporter gene expression following somatic gene transfer. In mice injected intravenously with replication-deficient adenovirus carrying a D2R reporter gene, PET in vivo measures of hepatic [18F] retention are proportional to in vitro measures of hepatic FESP retention, D2R ligand binding and D2R mRNA. We use tumor-forming cells carrying a stably transfected D2R gene to demonstrate imaging of this PET reporter gene/PET reporter probe system in 'tissues'. Tumors expressing the transfected D2R reporter gene retain substantially more FESP than control tumors. The D2R/FESP reporter gene/reporter probe system should be a valuable technique to monitor, in vivo, expression from both gene therapy vectors and transgenes.

Adenoviridae↗
PubMed1999

A study of artefacts in simultaneous PET and MR imaging using a prototype MR compatible PET scanner.

We have assessed the possibility of artefacts that can arise in attempting to perform simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) using a small prototype MR compatible PET scanner (McPET). In these experiments, we examine MR images for any major artefacts or loss in image quality due to inhomogeneities in the magnetic field, radiofrequency interference or susceptibility effects caused by operation of the PET system inside the MR scanner. In addition, possible artefacts in the PET images caused by the static and time-varying magnetic fields or radiofrequency interference from the MR system were investigated. Biological tissue and a T2-weighted spin echo sequence were used to examine susceptibility artefacts due to components of the McPET scanner (scintillator, optical fibres) situated in the MR field of view. A range of commonly used MR pulse sequences was studied while acquiring PET data to look for possible artefacts in either the PET or MR images. Other than a small loss in signal-to-noise using gradient echo sequences, there was no significant interaction between the two imaging systems. Simultaneous PET and MR imaging of simple phantoms was also carried out in different MR systems with field strengths ranging from 0.2 to 4.7 T. The results of these studies demonstrate that it is possible to acquire PET and MR images simultaneously, without any significant artefacts or loss in image quality, using our prototype MR compatible PET scanner.

Artifacts↗
PubMed1999

Performance evaluation of microPET: a high-resolution lutetium oxyorthosilicate PET scanner for animal imaging.

UNLABELLED: A new dedicated PET scanner, microPET, was designed and developed at the University of California, Los Angeles, for imaging small laboratory animals. The goal was to provide a compact system with superior spatial resolution at a fraction of the cost of a clinical PET scanner. METHODS: The system uses fiberoptic readout of individually cut lutetium oxyorthosilicate (LSO) crystals to achieve high spatial resolution. Each microPET detector consists of an 8 x 8 array of 2 x 2 x 10-mm LSO scintillation crystals that are coupled to a 64-channel photomultiplier tube by optical fibers. The tomograph consists of 30 detectors in a continuous ring with a 17.2-cm diameter and fields of view (FOVs) of 11.25 cm in the transaxial direction and 1.8 cm in the axial direction. The system has eight crystal rings and no interplane septa. It operates exclusively in the three-dimensional mode and has an electronically controlled bed that is capable of wobbling with a radius of 300 microm. We describe the performance of the tomograph in terms of its spatial, energy and timing resolution, as well as its sensitivity and counting-rate performance. We also illustrate its overall imaging performance with phantom and animal studies that demonstrate the potential applications of this device to biomedical research. RESULTS: Images reconstructed with three-dimensional filtered backprojection show a spatial resolution of 1.8 mm at the center of the FOV (CFOV), which remains <2.5 mm for the central 5 cm of the transaxial FOV. The resulting volumetric resolution of the system is <8 microL. The absolute system sensitivity measured with a 0.74 MBq (20 microCi) 68Ge point source at the CFOV is 5.62 Hz/kBq. The maximum noise equivalent counting rate obtained with a 6.4-cm diameter cylinder spanning the central 56% of the FOV is 10 kcps, whereas the scatter fraction is 37% at the CFOV for an energy window of 250-650 keV and the same diameter cylinder. CONCLUSION: This is the first PET scanner to use the new scintillator LSO and uses a novel detector design to achieve high volumetric spatial resolution. The combination of imaging characteristics of this prototype system (resolution, sensitivity, counting-rate performance and scatter fraction) opens up new possibilities in the study of animal models with PET.

Animals↗
PubMed1998

High-resolution 3D Bayesian image reconstruction using the microPET small-animal scanner.

A Bayesian method is described for reconstruction of high-resolution 3D images from the microPET small-animal scanner. Resolution recovery is achieved by explicitly modelling the depth dependent geometric sensitivity for each voxel in combination with an accurate detector response model that includes factors due to photon pair non-collinearity and inter-crystal scatter and penetration. To reduce storage and computational costs we use a factored matrix in which the detector response is modelled using a sinogram blurring kernel. Maximum a posteriori (MAP) images are reconstructed using this model in combination with a Poisson likelihood function and a Gibbs prior on the image. Reconstructions obtained from point source data using the accurate system model demonstrate a potential for near-isotropic FWHM resolution of approximately 1.2 mm at the center of the field of view compared with approximately 2 mm when using an analytic 3D reprojection (3DRP) method with a ramp filter. These results also show the ability of the accurate system model to compensate for resolution loss due to crystal penetration producing nearly constant radial FWHM resolution of 1 mm out to a 4 mm radius. Studies with a point source in a uniform cylinder indicate that as the resolution of the image is reduced to control noise propagation the resolution obtained using the accurate system model is superior to that obtained using 3DRP at matched background noise levels. Additional studies using pie phantoms with hot and cold cylinders of diameter 1-2.5 mm and 18FDG animal studies appear to confirm this observation.

Animals↗
PubMed1998

An evaluation of exact and approximate 3-D reconstruction algorithms for a high-resolution, small-animal PET scanner.

MicroPET is a low-cost, high-resolution positron emission tomography (PET) scanner designed for imaging small animals. MicroPET operates exclusively without septa, acquiring fully three-dimensional (3-D) data sets. The performance of the projection-reprojection (3DRP), variable axial rebinning (VARB), single slice rebinning (SSRB), and Fourier rebinning (FORE) methods for reconstruction of microPET data were evaluated. The algorithms were compared with respect to resolution, noise variance, and reconstruction time. Results suggested that the 3DRP algorithm gives the best combination of resolution and noise performance in 9 min of reconstruction time on a Sun UltraSparc I workstation. The FORE algorithm provided the most acceptable accelerated method of reconstruction, giving similar resolution performance with a 10%-20% degradation in noise variance in under 2 min. Significant degradation in the axial resolution was measured with the VARB and SSRB methods, offsetting the decrease in reconstruction time achieved with those methods. In-plane angular mashing of the 3-D data before reconstruction led to a 50% reduction in reconstruction time but also introduced unacceptable tangential blurring artifacts. This thorough evaluation of analytical 3-D reconstruction techniques allowed for optimal selection of a reconstruction method for the diverse range of microPET applications.

Algorithms↗
PubMed1998

Noninvasive methods for quantitating blood time-activity curves from mouse PET images obtained with fluorine-18-fluorodeoxyglucose.

UNLABELLED: The mouse model is currently being explored for various applications with PET imaging. Low resolution of current animal scanners relative to mouse size leads to difficulty in quantitating data from mouse PET images. We have, therefore, investigated methods for determining blood time-activity curves (TACs) from mouse PET studies done with fluorine-18-fluorodeoxyglucose (FDG). METHODS: Eight mice were fasted, the tail vein was injected with 150-300 microCi of FDG and dynamic images were acquired with a CTI/Siemens (Knoxville, TN) animal tomograph for 64.5 min. Concurrently, 11-14 left ventricle (LV) blood samples were drawn directly from the LV chamber. Organ TACs were obtained by drawing circular regions of interest (ROIs) of various sizes on images of the heart, liver and brain. For each mouse, the FDG model parameter K = (K1 x k3)/(k2 + k3) was estimated by a Patlak algorithm with various estimates of the blood TAC and, as a reference tissue TAC, the brain TAC. RESULTS: Most partial-volume-corrected heart ROI TACs overestimated the LV samples. Blood TACs from heart images produced statistically different estimates of K than did the LV samples. The liver image-derived blood TACs yielded estimates of K that were comparable to those yielded by the LV samples. Estimates of K determined with two directly sampled LV points in conjunction with the liver image-derived TAC were not statistically different from the estimates obtained with the LV samples. The size and location of ROIs on images of the liver minimally affected the TACs. CONCLUSION: We have shown that it is experimentally possible to obtain a blood TAC from mouse studies by repeatedly sampling from the LV. We have also shown that images of the liver can be used to reliably estimate the blood TAC. Future FDG PET studies with the mouse model will benefit from this demonstrated ability to noninvasively quantitate blood TACs directly from FDG PET images.

Animals↗
PubMed1998

Evaluation of the detectability of breast cancer lesions using a modified anthropomorphic phantom.

UNLABELLED: During the development and characterization of imaging technology or new imaging protocols, it is usually instructive to perform phantom experiments. Often, very simplified forms of the realistic patient anatomy are used that may be acceptable under certain conditions; however, the implications for patient studies can be misleading. This is particularly true in breast and axillary node imaging. The complexities presented by the anatomy, variable object scatter, attenuation and inhomogeneous distribution of activity in this upper thoracic region provide a significant challenge to the imaging task. METHODS: A tissue-equivalent anthropomorphic phantom of the thorax (Radiology Support Devices, Inc., Long Beach, CA) containing fillable cavities and organs was modified for the studies. The phantom was filled with realistic levels of FDG activity and scanned on a Siemens ECAT HR+ whole-body PET scanner. Breast attachments containing 2.0- and 2.55-cc lesions with lesion-to-background ratios of 5:1 and 7:1, respectively, were imaged. Scatter and attenuation effects were analyzed with various experimental setups. A lymph node experiment and a multibed position whole-phantom scan also were performed to illustrate the extent to which the phantom represents the human thorax. RESULTS: Regions of interest were drawn on the lesions as well as the background breast tissue in all studies. It was found that the signal-to-noise ratio decreased 65% when a more realistic phantom (lesions plus breasts plus thorax, all containing activity) was used, as compared to a simple phantom (lesions plus breasts containing activity; no thorax), due to the effects of increased scatter and attenuation. A 23% decrease in the contrast also was seen from the scan of the more realistic phantom due to surrounding activity from nearby organs such as the heart, as well as an increase in the volume of attenuating media. CONCLUSION: This new phantom allows us to more realistically model the conditions for breast and lymph node imaging, leading to preclinical testing that will produce results that better approximate those that will be found in vivo. The phantom will be a valuable tool in comparing different imaging technologies, data collection strategies and image reconstruction algorithms for applications in breast cancer using PET, SPECT or scintimammography systems.

Axilla↗
PubMed1998

Imaging of adenoviral-directed herpes simplex virus type 1 thymidine kinase reporter gene expression in mice with radiolabeled ganciclovir.

UNLABELLED: We are developing procedures to repeatedly and noninvasively image the expression of transplanted reporter genes in living animals and in patients, using PET. We have investigated the use of the Herpes Simplex Virus type 1 thymidine kinase gene (HSV1-tk) as a reporter gene and [8-14C]-ganciclovir as a reporter probe. HSV1-tk, when expressed, leads to phosphorylation of [8-14C]-ganciclovir. As a result, specific accumulation of phosphorylated [8-14C]-ganciclovir should occur almost exclusively in tissues expressing the HSV1-tk gene. METHODS: An adenoviral vector was constructed carrying the HSV1-tk gene along with a control vector. C6 rat glioma cells were infected with either viral vector and uptake of [8-3H]-ganciclovir was determined. In addition, 12 mice were injected with varying levels of either viral vector. Adenovirus administration in mice leads primarily to liver infection. Forty-eight hours later the mice were injected with [8-14C]-ganciclovir, and 1 hr later the mice were sacrificed and biodistribution studies performed. Digital whole-body autoradiography also was performed on separate animals. HSV1-tk expression was assayed, using both normalized HSV1-tk mRNA levels and relative HSV1-TK enzyme levels, in both the cell culture and murine studies. RESULTS: Cell culture, murine tissue biodistribution and murine in vivo digital whole-body autoradiography all demonstrate the feasibility of HSV1-tk as a reporter gene and [8-14C]-ganciclovir as an imaging reporter probe. A good correlation (r2 = 0.86) between the [8-14C]-ganciclovir percent injected dose per gram tissue from HSV1-tk positive tissues and HSV1-TK enzyme levels in vivo was found. An initial study in mice with [8-18F]-fluoroganciclovir and microPET imaging supports further investigation of [8-18F]-fluoroganciclovir as a PET reporter probe for imaging HSV1-tk gene expression. CONCLUSION: These results demonstrate the feasibility of using [8-14C]-ganciclovir as a reporter probe for the HSV1-tk reporter gene, using an in vivo adenoviral mediated gene delivery system in a murine model. The results form the foundation for further investigation of [8-18F]-fluoroganciclovir for noninvasive and repeated imaging of gene expression with PET.

Adenoviridae↗