F-FDG microPET Research Articles

Effects of curcumin on glucose metabolism in the brains of rats subjected to chronic unpredictable stress: a 18 F-FDG micro-PET study

BackgroundChronic unpredictable stress (CUS) can cause behavioral and physiological abnormalities that are important to the prediction of symptoms of depression that may be associated with cerebral glucose metabolic abnormalities. Curcumin showed potential antidepressant effects, but whether or not it can reverse cerebral functional abnormalities and so ameliorate depression remains unknown.MethodsTo investigate the effects of curcumin on brain activity in CUS rats, rats were subjected to 3 weeks of CUS and then treated with curcumin orally at a dose of 40 mg/kg/day for one month. 18 F fluorodeoxyglucose (18 F-FDG)-micro positron emission tomography (micro-PET) neuroimaging was used to detect changes in cerebral metabolism. Body weight, sucrose preference, and open field tests were used to record depressive behaviors during CUS and after curcumin treatment.ResultsThree weeks of CUS significantly decreased body weight, sucrose preference, sucrose consumption, total distance travelling, and the number of rearing events. It also induced metabolic alterations in several parts of the brain, showing increased glucose metabolism in the right hemisphere. After curcumin treatment for one month, sucrose preference, sucrose consumption, total distance travelling, and the number of rearing events returned to normal levels. Curcumin treatment also induced strong deactivation of the left primary auditory cortex and activation of amygdalohippocampal cortex.ConclusionCurcumin was found to ameliorate the abnormalities in the behavior and brain glucose metabolism caused by CUS, which may account for its antidepressive effects.

Noninvasive Estimation of the Input Function for Dynamic Mouse <formula formulatype="inline"><tex Notation="TeX"> $^{\bf 18}$</tex></formula>F-FDG MicroPET Studies

A new noninvasive estimation method for the plasma time-activity curve, i.e., input function (IF) of the tracer kinetic model in dynamic (18)F-FDG microPET mouse studies, is proposed and validated. This estimation method comprises of four steps. First, a novel constraint nonnegative matrix factorization segmentation algorithm was applied to extract the left ventricle (Lv) and myocardium (Myo) time activity curves (TACs). Second, we modeled the IF as a seven-parameter mathematical equation and constructed a dual-output model of the real TAC in Lv and Myo accounting for the partial-volume and spillover effects. Then, we fit the image-derived Lv and Myo TACs to the dual-output model to estimate the parameters of the IF. Finally, the IF was validated by comparing it to the gold standard IF while considering the delay and dispersion effects. Our method was verified based on 20 mice datasets from the Mouse Quantitation Program database, provided by UCLA. The error of the areas under the curves between the delayed and dispersed estimated IF and the gold standard IF was 7.237% ± 6.742% (r = 0.969), and the error of the (18)F-FDG influx constant Ki of the Myo was 4.910% ± 6.810% ( r = 0.992). The results demonstrated the effectiveness of the proposed method.

Reproducibility of Static and Dynamic 18F-FDG, 18F-FLT, and 18F-FMISO MicroPET Studies in a Murine Model of HER2+ Breast Cancer

The objective of this study is to determine the reproducibility of static 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG), 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT), and [(18)F]-fluoromisonidazole ((18)F-FMISO) microPET measurements, as well as kinetic parameters returned from analyses of dynamic (18)F-FLT and (18)F-FMISO data. HER2+ xenografts were established in nude mice. Dynamic data were acquired for 60min, followed by a repeat injection and second scan 6h later. Reproducibility was assessed for the percent-injected dose per gram (%ID/g) for each radiotracer, and with kinetic parameters (K (1) -k (4) , K ( i )) for (18)F-FLT and (18)F-FMISO. The value needed to reflect a change in tumor physiology is given by the 95% confidence interval (CI), which is ±14, ±5, and ±6% for (18)F-FDG (n = 12), (18)F-FLT (n = 11), and (18)F-FMISO (n = 11) %ID/g, respectively. V ( d ) (=K (1) /k (2)), k (3), and K (FLT) are the most reproducible (18)F-FLT (n = 9) kinetic parameters, with 95% CIs of ±18, ±10, and ±18%, respectively. V ( d ) and K (FMISO) are the most reproducible (18)F-FMISO kinetic parameters (n = 7) with 95% CIs of ±16 and ±14%, respectively. Percent-injected dose per gram measurements are reproducible and appropriate for detecting treatment-induced changes. Kinetic parameters have larger threshold values, but are potentially sufficiently reproducible to detect treatment response.

Abstract 250: Increased 18F-FDG Uptake in the Aortic Wall of β-Aminopropionitrile Exposed Rats May Be Predictive of AAA Rupture

Objectives: Ruptured abdominal aortic aneurysm (AAA) is associated with a high mortality rate, and a noninvasive test is necessary to detect vascular wall inflammation that may aid in predicting AAA rupture. The ability of 18F-FDG positron emission tomography (PET) imaging to identify increased inflammation in the porcine pancreatic elastase (PPE) perfusion model in Sprague-Dawley rats exposed to β-aminopropionitrile (BAPN) to stimulate AAA rupture was evaluated. Methods: Starting 3d prior to infrarenal abdominal aortic exposure to PPE, BAPN (300mg/kg subcutaneous) was administered daily until AAA harvest or rupture (BAPN, n=9). Control rats only underwent PPE exposure (n=8). Aortic diameter was evaluated at 3, 7, and 14d post PPE exposure utilizing ultrasound (US, 12MHz). Both groups were imaged with 18F-FDG microPET (control n=4, rupture n=3) 7d post PPE exposure. Maximum AAA to mean muscle 18F-FDG uptake ratios (AMR) were determined. Matrix metalloproteinase (MMP) 2 and 9 zymogramatic activities, in terms of integrated optical density (IOD), were assessed at 7d (control n=3, BAPN n=4) and 14d post PPE exposure (control n=3, rupture n=3). Results: Mean 7d aortic diameter increases of 247% and 398% (p=0.014) were observed in control and rupture groups, respectively, with no evidence of dissection in BAPN exposed rats on US. Three BAPN exposed rats ruptured within 24h after 18F-FDG microPET, with mean AMRs for the control and ruptured groups of 86.5 and 281.9 (p=0.048), respectively. IOD values of 4655 and 8373 (p=0.140) were determined for MMP9 activity in 14d control and ruptured AAA tissue, respectively, representing an 80% increase in ruptured AAA tissue. IOD values of 4760 and 1190 (p=0.032) were determined for MMP2 activity in 14d control and ruptured AAA tissue, respectively, representing a 75% decrease in ruptured AAA tissue. No differences in MMP2 or 9 activities for control and BAPN exposed rats were observed at 7d post PPE exposure. Conclusions: Alterations in MMP2 and 9 activities in BAPN exposed, ruptured, rat AAA tissues parallel alterations in MMP2 and 9 activities in ruptured, human AAA tissues observed by others. Increased 18F-FDG uptake by rat AAAs that subsequently ruptured suggests that FDG-PET may be used to predict AAA rupture in humans.

Abstract 529: Increased 18F-FDG Uptake in the Aortic Wall of β-aminopropionitrile Exposed Rats May be Predictive of AAA Rupture

Objectives: Ruptured abdominal aortic aneurysm (AAA) is associated with a uniformly high mortality rate, and a noninvasive method is necessary to detect vascular wall inflammation that may assist in predicting AAA rupture. The ability of 18F-FDG positron emission tomography to identify increased inflammation in the porcine pancreatic elastase (PPE) perfusion model in Sprague-Dawley rats exposed to β-aminopropionitrile (BAPN) to stimulate AAA rupture was evaluated. Methods: BAPN (300mg/kg subcutaneous) was administered daily starting 3d prior to infrarenal abdominal aortic exposure to PPE and daily until AAA harvest or rupture (BAPN, n=10). Control rats only underwent PPE exposure (n=8). Aortic diameter was evaluated at 3, 7, and 14d post PPE exposure utilizing ultrasound (US, 12MHz). Both groups were imaged with 18F-FDG microPET. AAA maximum to mean muscle 18F-FDG uptake ratios (AMR) were determined. AAA rupture sites were identified at post rupture harvest. Matrix metalloproteinase (MMP) 2 and 9 zymogramatic activities, in terms of integrated optical density (IOD), were assessed at 7d (control n=3, BAPN n=4) and 14d post PPE exposure (control n=3, rupture n=3). Results: Mean 7d aortic diameter increases of 251 ± 29.4% and 340 ± 56.0% (p=0.20) were observed in control and rupture groups, respectively. Four BAPN exposed rats ruptured within 24h after 18F-FDG microPET. Considering the entire AAA, mean AMRs for control and ruptured groups were not significantly different at 15.3 ± 1.6 and 15.5 ± 1.9, respectively. However, considering the 18F-FDG uptake at known rupture sites, the mean AMR for ruptured AAAs was significantly greater than that of control AAAs (AMR 13.2 ± 1.1 vs. 8.4 ± 1.3, p=0.02). IOD values of 8373 ± 827 and 4655 ± 1851 (p=0.14) were observed for MMP9 activity in 14d control and ruptured AAA tissue, representing an 80% increase in ruptured AAA tissue. IOD values of 4760 ± 647 and 1190 ± 87 (p=0.03) were observed for MMP2 activity in 14d control and ruptured AAA tissue, respectively, representing a 75% decrease in ruptured AAA tissue. No differences in MMP2 or 9 activities for control and BAPN exposed rats were appreciated at 7d post PPE exposure. Conclusions: Increased MMP9 activity in ruptured rat AAA tissue parallels what has been observed in ruptured human AAA tissue. Decreased MMP2 activity in ruptured AAA tissue may represent decreased smooth muscle cell presence. Increased 18F-FDG uptake by rat AAA walls, in regions of known rupture, suggests that FDG-PET may be used to predict AAA rupture.

Abstract 2439: Molecular imaging of spatial and temporal heterogeneity of tumor micro-environment in mouse models of non-small cell lung cancer macroscopic xenografts and micro-metastases

Abstract 18F-fluoro-2-deoxyglucose (18F-FDG, imaging glucose metabolism), 18F-fluorothymidine (18F-FLT, cell proliferation) and 18F-misonidazole (18F-FMISO, hypoxia) PET scans have emerged as important clinical tools for management of cancer. The objective of this study was to spatially and temporally visualize tumor microenvironment of tumor hypoxia, proliferation and glucose metabolism using 18F-FDG, 18F-FLT and 18F-FMISO digital autoradiography and microPET comparing with histological findings. Methods: We used human non-small cell lung cancer (NSCLC) A549 and HTB177 cells to generate subcutaneous and peritoneal metastases in nude mice. Animals were coinjected with the mixture of one PET radiotracer, pimonidazole (hypoxia marker) and bromodeoxyuridine (proliferation marker) intravenously 1 hour before animal euthanasia. The intratumoral distributions of radiotracers were visualized by digital autoradiography (DAR) and related to microscopic visualization of cellular proliferation, tumor hypoxia, stroma and necrosis. Serial microPET scans (day 1to day5) were also performed in the same animals to investigate change in glucose metabolism (using 18F-FDG), proliferation (18F-FLT) and hypoxia (18F-FMISO). Results: NSCLC microenvironment was complex and highly heterogeneous: xenografts had complex structures with intermingled regions of well oxygenated (negative pimonidazole) and highly proliferative (positive bromodeoxyuridine) cancer cells, hypoxic (positive pimonidazole) and low proliferation (little bromodeoxyuridine) cancer cells stroma and necrosis. Hypoxic cancer cells had high18F-FDG and 18F-FMISO but low 18F-FLT accumulation, indicating increased glucose metabolism is not a common feature of cancer cells but only hypoxic ones. Well oxygenated cancer cells with high proliferation rate accumulated high level of 18F-FLT, but low 18F-FDG and18F-FMISO. Stroma and necrotic zones always associated with low activity in all radiotracers we tested. MicroPET scans revealed apparent change in intratumor distribution of 18F-FLT, 18F-FDG as well as 18F-FMISO in as short as ∼48 hrs interval, indicating temporal heterogeneity of tumor microenvironment in term of proliferation, glucose metabolism and hypoxia. Conclusions: Both macroscopic xenografts and micrometastases of NSCLC have spatial heterogeneity of tumor microenvironment. Temporal change of tumor microenvironment did occur in a very short of interval of natural growth process in NSCLC. We have investigated to spatial and temporal behavior of heterogeneity of tumor microenvironment which is important for better understanding cancer biology and cancer management, if our findings in mice models are clinically applicable. Acknowledgement: This study was supported by Kentucky Lung Cancer Research Program Award to Dr. Xiao-Feng Li. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2439. doi:1538-7445.AM2012-2439

18F‐FDG microPET imaging detects early transient response to an IGF1R inhibitor in genetically engineered rhabdomyosarcoma models

Alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) are among the most common and most treatment resistant soft tissue sarcomas of childhood. Here, we evaluated the potential of (18)F-Fluorodeoxyglucose (FDG) as a marker of therapeutic response to picropodophyllin (PPP), an IGF1R inhibitor, in a conditional mouse model of ARMS and a conditional model of ERMS/undifferentiated pleomorphic sarcoma (UPS). Primary tumor cell cultures from Myf6Cre,Pax3:Fkhr,p53 and Pax7CreER,Ptch1,p53 conditional models of ARMS and ERMS/UPS were found to be highly sensitive to PPP (IC(50) values 150 and 200 nM, respectively). Animals of each model were then treated with 80 mg/kg/day PPP by intraperitoneal injection for 12 days and imaged by (18)F-FDG microPET. Tumor volumes on day 4 for PPP-treated ARMS and ERMS mice were lower than untreated control mouse tumor volumes, although treated tumors were larger than day 0. However, tumor FDG uptake was significantly reduced on day 4 for PPP-treated mice compared to pretreatment baseline or untreated control mice on day 4 (P < 0.05). Nevertheless, by day 12 tumor volumes and FDG uptake for treated mice had increased significantly, indicating rapidly evolving resistance to therapy. (18)F-FDG PET imaging is a potential imaging biomarker of molecular susceptibility to targeted agents early in treatment for this aggressive form of sarcoma, but may find best use serially for Phase I/II studies where chemotherapy and targeted agents are combined to cytoreduce tumors and abrogate Igf1r inhibitor resistance.

Use of 18F-FDG micro-PET and autoradiography to assess inflammation associated with rat abdominal aortic aneurysm formation

Use of 18F-FDG micro-PET and autoradiography to assess inflammation associated with rat abdominal aortic aneurysm formation Sean J English MD, Morand R Piert MD, Phillip S Sherman BSc, Carole A Quesada BSc, Lawrence T Holt NA, Paul D DiMusto MD, Jose A Diaz MD, Peter K Henke MD, FACS, Gilbert R Upchurch Jr MD, FACS University of Michigan/Conrad Jobst Vascular Laboratory, Ann Arbor, MI and University of Virginia, Charlottesville, VA

A study of microPET for assessing regional cerebral glucose metabolism and the expression of dopamine receptor type 2 in a rat model of Parkinson's disease

To employ (18)F-fluoro-2-deoxyglucose ((18)F-FDG) and (3-N-[(11)C] methylspiperone)(11)C-NMSP microPET to assess the changes of regional cerebral glucose metabolism and the expression of dopamine receptor type 2 (DRD(2)) in a rat model of Parkinson's disease (PD). A hemiparkinsonian model was established in rats by unilateral pretreatment with 6-hydroxydopamine (6-OHDA). At 2 weeks after 6-OHDA insult, (18)F-FDG and (11)C-NMSP microPET scan were performed to compare the differences of regional cerebral glucose metabolism and the expression of DRD(2) between the PD and control groups respectively. The immunohistochemical staining was used to detect the expression of tyrosine hydroxylase in two groups. In the PD model, the glucose metabolism rates were 88.2% ± 2.2%, 94.5% ± 4.5% and 96.2% ± 5.8% respectively, in right striatum, hippocampus and sensorimotor cortex. And they were significantly lower than those in the control group [92.7% ± 2.8% (P < 0.01), 98.9% ± 3.9% (P < 0.01) & 102.8% ± 2.1% (P < 0.01)]. The expression of DRD(2) in right striatum was significantly higher in the PD group than that in the control group (112.9% ± 9.0% vs 102.3% ± 1.4%, P < 0.01). In the PD rats, glucose metabolism decreases in injured side striatum, hippocampus and sensorimotor cortex while and the expression of DRD(2) increases in injured side striatum.(18)F-FDG and (11)C-NMSP microPET can effectively assess the regional cerebral glucose metabolism and the expression of DRD(2) in PD. They may serve as effective molecular imaging tools for an early diagnosis of PD.

Using 18F-FDG microPET imaging to measure the inhibitory effects of Clematis chinensis Osbeck on the pro-inflammatory and degradative mediators associated with inflammatory arthritis

This study examined the modulating effects of Clematis chinensis Osbeck (Ranunculaeae) on pro-inflammatory and degradative mediators associated with inflammatory arthritis. Primary human chondrocytes (PHC) were stimulated with IL-1β or lipopolysaccharide (LPS) to induce the enhanced release of prostaglandin E(2) (PGE(2)), metalloproteinase (MMP-3 and -13), and cyclooxygenase-2 (COX-2) protein expression. The (18)F-FDG microPET imaging system was used to evaluate the anti-arthritic effects of Clematis chinensisin vivo. The acetone extracted Clematis chinensis (CC6) contained the most total saponins compared to other solvent's extracts and showed significant and dose-dependent inhibitory effects on PGE(2), MMP-3, -13, and COX-2 productions by LPS-stimulated PHC. Furthermore, CC6 also exerted inhibitory effects on 2-(18)F-fluoro-2-deoxy-d-glucose ((18)F-FDG) uptake when assessed by positron emission tomography (PET) uptake in the joints and serum PGE(2) of rabbits with knee joints injected with LPS. The results suggest the significant chondroprotective effects of Clematis chinensis are through its anti-inflammatory and MMPs inhibitory abilities. Meanwhile, we established a new analysis method to evaluate the Chinese herbal anti-arthritic effects.

Evaluation of biodistribution and antitumor effects of 188Re-rhk5 in a mouse model of lung cancer

Targeting drugs to receptors involved in tumor angiogenesis is considered to be a novel and promising approach to improve cancer treatment. This study aimed to evaluate the anti-tumor efficacy of (188)Re-labeled recombinant human plasminogen kringle 5 ((188)Re‑rhk5) through [18F]-fluorodeoxyglucose (FDG) micro-positron emission tomography (PET). Radiolabeled rhk5 was obtained by conjugating the hystidine (6 x His) group at the carbon end of rhk5 with fac-[(188)Re(H(2)O)(3)(CO)(3)](+). The biodistribution study of (188)Re-rhk5 showed that (188)Re-rhk5 had a high initial tumor uptake and prolonged tumor retention. The highest tumor uptake of (188)Re-rhk5 (3.65±0.82%ID/g) was found 2 h after injection which decreased to 0.81±0.14%ID/g 12 h after injection. Following therapy, tumor size measurement indicated that (188)Re-rhk5-treated tumors were smaller than (188)Re-, rhk5- and saline-treated controls 6 days after the treatment. Invivo 18F-FDG micro-PET imaging showed significantly reduced tumor metabolism in the (188)Re-rhk5-treated mice vs. those treated with rhk5, (188)Re and saline control, 1 day after treatment. Moreover, the number of microvessels was significantly reduced after (188)Re-rhk5 treatment as determined by CD31 staining. Our results demonstrate that specific delivery of (188)Re-rhk5 allows preferential cytotoxicity to A549 lung cancer cells and tumor vasculature. (18)F-FDG micro-PET is a non-invasive imaging tool that can be utilized to assess early tumor responses to (188)Re-rhk5 therapy.

Anti-Inflammatory Effects of Resveratrol and Oligostilbenes from Vitis thunbergii var. taiwaniana against Lipopolysaccharide-Induced Arthritis

Vitis thunbergii Sieb. and Zucc. var. taiwaniana Lu is an endemic plant in Taiwan used as a dietary supplement for bone health. In this study, human chondrocytes were induced to produce COX-2, MMP-3, -13, and PGE(2) by LPS. An (18)F-FDG microPET imaging system was used to evaluate the anti-inflammatory arthritic effects in vivo. Six stilbenes, resveratrol (1), (+)-ε-viniferin (2), ampelopsin C (3), ampelopsin A (4), (-)-vitisin B (5), and (+)-vitisin A (6), were isolated from the stem part of V. thunbergii, which displayed the strongest PGE(2) inhibition. Among these compounds, 1 significantly decreased COX-2 activity, PGE(2), MMP-3, and -13 production in vitro, and (18)F-FDG uptake and serum PGE(2) in rabbits in vivo. Anti-inflammatory effects were enhanced through the combined usage of 1 and other oligostilbenes. Taken together, the synergistic effects of 1 and oligostilbenes resulted in stem part extracts with lower 1 content displaying the better anti-inflammatory arthritis effects.

Evaluation of an Intraperitoneal Ovarian Cancer Syngeneic Mouse Model Using18F-FDG MicroPET Imaging

The objective of this study was to evaluate the syngeneic immunocompetent mouse model by using the micro-positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (F-FDG microPET) imaging of ovarian tumor growth. ID8 ovarian carcinoma cells derived from C57BL/6 mice were intraperitoneally injected into female C57BL/6 mice. Mice were injected with F-FDG (7.4 MBq, intravenous injection), and microPET images were obtained 40 minutes later. Micro-computed tomographic images were also obtained immediately after microPET images for anatomical reference. F-FDG microPET images were acquired at baseline and at 4, 8, 10, and 11 weeks after tumor cell injection. The maximum standardized uptake value (SUVmax) in each time point was obtained from the images and compared to follow the tumor growth. Physiological uptake of F-FDG was intensely found in the bladder and heart and frequently in the gastrointestinal tract. Diffused uptake of F-FDG was observed in the peritoneal cavity of all tumor-bearing mice at 4 weeks, and high focal uptakes were developed in the peritoneal cavity at 8 to 11 weeks. High focal uptakes increased over time, correlating with a progressive increase in the SUVmax of F-FDG. At 11 weeks, the SUVmax value was significantly increased (1.49 ± 0.10 at 11 weeks vs 0.29 ± 0.03 at baseline, P < 0.01). Tumors in the gut and peritoneum were confirmed by anatomical and histopathological examination. Our results demonstrate that the peritoneal tumor growth in the syngeneic ovarian cancer model can be detected by the F-FDG microPET imaging.

Brown Adipose Tissue Can Be Activated or Inhibited within an Hour before 18F‐FDG Injection: A Preliminary Study with MicroPET

Brown adipose tissue (BAT) is emerging as a potential target for treating human obesity. It has been indicated that BAT is rich in innervations of sympathetic nerve control. Using 18F-FDG microPET imaging, this study aims at evaluating how factors related to sympathetic activation/inhibition changed BAT metabolism of mice. BAT 18F-FDG uptake were semiquantitatively evaluated in different groups of mice under temperature (cold or warm stimulus) or pharmacological interventions (norepinephrine, epinephrine, isoprenaline, or propranolol) and were compared with the corresponding controls. It was found that BAT activation can be stimulated by cold exposure (P = 1.96 × 10−4), norepinephrine (P = .002), or both (P = 2.19 × 10−6) within an hour before 18F-FDG injection and can also be alleviated by warming up (P = .001) or propranolol lavage (P = .027). This preliminary study indicated that BAT function could be evaluated by 18F-FDG PET imaging through short-term interventions, which paved the way for further investigation of the relationship between human obesity and BAT dysfunction.

Morphological, functional and metabolic imaging biomarkers: assessment of vascular-disrupting effect on rodent liver tumours

To evaluate effects of a vascular-disrupting agent on rodent tumour models. Twenty rats with liver rhabdomyosarcomas received ZD6126 intravenously at 20 mg/kg, and 10 vehicle-treated rats were used as controls. Multiple sequences, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) with the microvascular permeability constant (K), were acquired at baseline, 1 h, 24 h and 48 h post-treatment by using 1.5-T MRI. [(18)F]fluorodeoxyglucose micro-positron emission tomography ((18)F-FDG microPET) was acquired pre- and post-treatment. The imaging biomarkers including tumour volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC) and K from MRI, and maximal standardised uptake value (SUV(max)) from FDG microPET were quantified and correlated with postmortem microangiography and histopathology. In the ZD6126-treated group, tumours grew slower with higher necrosis ratio at 48 h (P < 0.05), corresponding well to histopathology; tumour K decreased from 1 h until 24 h, and partially recovered at 48 h (P < 0.05), parallel to the evolving enhancement ratios (P < 0.05); ADCs varied with tumour viability and perfusion; and SUV(max) dropped at 24 h (P < 0.01). Relative K of tumour versus liver at 48 h correlated with relative vascular density on microangiography (r = 0.93, P < 0.05). The imaging biomarkers allowed morphological, functional and metabolic quantifications of vascular shutdown, necrosis formation and tumour relapse shortly after treatment. A single dose of ZD6126 significantly diminished tumour blood supply and growth until 48 h post-treatment.

Positron emission tomography imaging of DMBA/TPA mouse skin multi-step tumorigenesis

Many tumor cells have elevated rates of glucose uptake that can be measured quantitatively, noninvasively and repeatedly by positron emission tomography (PET) with 2-deoxy-2-[ 18F]-fluoro-D-glucose ( 18F-FDG). Clinical imaging with 18F-FDG PET has been used for detection and staging of primary and metastatic tumors. High-resolution microPET scanning and murine cancer models make it possible to analyze longitudinally glucose metabolism during the appearance, development and progression of individual experimental tumors. In this study, we used 18F-FDG microPET and micro computerized tomography (microCT) to investigate glucose uptake in the DMBA/TPA chemically-induced multistage mouse skin carcinogenesis model. 18F-FDG uptake is significantly higher in all papillomas than in surrounding skin. Elevated 18F-FDG uptake is observed when tumors can be identified morphologically, but not before. Although 18F-FDG uptake is high in all fully invasive, malignant skin squamous cell carcinomas, uptake in papillomas and microinvasive malignant squamous cell carcinomas is variable and does not exhibit any correlation with tumor stage.

Protective effects of repetitive transcranial magnetic stimulation in a rat model of transient cerebral ischaemia: a microPET study

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method to excite neurons in the brain. However, the underlying mechanism of its therapeutic effects in stroke remains unclear. The aim of this study was to investigate the neuroprotective effect of high-frequency rTMS in a rat model of transient cerebral ischaemia using positron emission tomography (PET). Sprague-Dawley rats (n=30) were anaesthetized with chloral hydrate and subjected to 90 min of intraluminal middle cerebral artery occlusion (MCAO) with subsequent reperfusion in three groups: control (n=10), rTMS (n=10), or sham-rTMS groups (n=10). In the rTMS group, rTMS was given 1 h after ischaemia and every 24 h for 7 days after MCAO. In all three groups, small-animal PET (microPET) imaging with (18)F-FDG was used to evaluate brain glucose metabolism. Apoptotic molecules were measured in the infarct margin using immunohistochemical staining. The neurological scores of the rats in the rTMS group were higher than in those of the control group over the whole 7-day observation period. The total, cortical and striatal infarct volumes were significantly less in the rTMS group than in the control group, as measured by 2,3,5-triphenyltetrazolium chloride staining. (18)F-FDG microPET images showed significantly higher standardized uptake values in the cortex and striatum in the rTMS group than in the control group in the affected hemisphere. The number of cells positive for caspase-3 was significantly lower in the rTMS group than in the control group, while the Bcl-2/Bax ratio was significantly higher in the rTMS group than in the control group. rTMS therapy increased glucose metabolism and inhibited apoptosis in the ischaemic hemisphere. (18)F-FDG PET could be used to monitor rTMS therapy in transient cerebral ischaemia in animal studies and in future clinical trials.

Evaluation of a rat knee mono-arthritis using microPET

Assessing the activity of synovitis, which is characterized by an increase in cell metabolism, is important for the prediction of future articular destruction in clinical and preclinical studies. To evaluate the correlation between ¹⁸F-FDG accumulation and arthritis pathology during its establishment, we used microPET to evaluted ¹⁸F-FDG accumulation in vivo during rat Mycobacterium wall-induced knee arthritis. ¹⁸F-FDG PET images of arthritic rats were acquired on days 1, 2, 3 and 7 after arthritis induction. The subjects (n=2/time) were subsequently subjected to macro-autoradiography, and ¹⁸F-FDG accumulation was compared with histological findings. ¹⁸F-FDG PET images depicted swollen joints, and ¹⁸F-FDG accumulation increased with the progression of arthritis. Histologically, increased ¹⁸F-FDG accumulation correlated with the pannus rather than the infiltration of inflammatory cells around the joints. ¹⁸F-FDG accumulation in arthritis reflects proliferating pannus and inflammatory activity enhanced by inflammatory cytokines. ¹⁸F-FDG microPET should be effective for quantifying the inflammatory activity of arthritis and/or its therapeutic response.

Imaging a pancreatic carcinoma xenograft model with 11C-acetate: a comparison study with 18F-FDG

Pancreatic carcinoma is a malignant tumor with poor prognosis and its early detection is still a clinical problem. The aim of this study was to evaluate the efficacy of carbon-11-labeled acetate (11C-acetate)-positron emission tomography (PET) for the detection of pancreatic carcinoma in a BxPC-3 human pancreatic carcinoma xenograft-bearing immunodeficiency BALB/c-nu nude mice model. Whole-body 11C-acetate and fluorine-18-labeled fluorodeoxyglucose (F-FDG) micro-PET imaging were performed weekly on BxPC-3 human pancreatic carcinoma xenograft-bearing BALB/c-nu nude mice from the 2nd week after tumor cell inoculation. Regions of interest method and tumor-to-nontumor ratio (T/N ratio) were used for semiquantitative evaluation. Tumor proliferation was evaluated by immunohistochemistry analysis of proliferating cell nuclear antigen. Radiotracer accumulation in the tumor xenografts could be detected 1 week earlier in 11C-acetate-PET than that in 18F-FDG-PET. Peak T/N ratio was obtained at the 5th week in 11C-acetate-PET and at the 4th week in 18F-FDG-PET. T/N ratio in 11C-acetate-PET was lower than that in 18F-FDG-PET during the same period. By visual evaluation, tumor xenografts were more easily observed in 11C-acetate-PET than in 18F-FDG-PET in most of the mice. Linear correlation analysis indicated T/N ratios in C-acetate-PET had no significant correlation with those in 18F-FDG-PET. Tumor size, T/N ratio in 11C-acetate-PET, and T/N ratio in 18F-FDG-PET were not found to be significantly correlated with tumor proliferating cell nuclear antigen expression. 11C-acetate-PET imaging can be used for the detection of pancreatic carcinoma. In the early stage of tumor growth, 11C-acetate-PET has better detectability than that of 18F-FDG-PET.

Micro-Positron Emission Tomography in the Evaluation of Trypanosoma cruzi-Induced Heart Disease: Comparison with Other Modalities

Noninvasive assessment of cardiac structure and function is essential to understand the natural course of murine infection with Trypanosoma cruzi. Magnetic resonance imaging (MRI) and echocardiography have been used to monitor anatomy and function; positron emission tomography (PET) is ideal for monitoring metabolic events in the myocardium. Mice infected with T. cruzi (Brazil strain) were imaged 15-100 days post infection (dpi). Quantitative (18)F-FDG microPET imaging, MRI and echocardiography were performed and compared. Tracer ((18)F-FDG) uptake was significantly higher in infected mice at all days of infection, from 15 to 100 dpi. Dilatation of the right ventricular chamber was observed by MRI from 30 to 100 dpi in infected mice. Echocardiography revealed significantly reduced ejection fraction by 60 dpi. Combination of these three complementary imaging modalities makes it possible to noninvasively quantify cardiovascular function, morphology, and metabolism from the earliest days of infection through the chronic phase.