Serial Positron Emission Tomography Imaging Research Articles

Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging

Blockade of signaling through the epidermal growth factor receptor (EGFR) tyrosine kinase by inhibitors such as gefitinib (Iressa) can inhibit tumor angiogenesis and enhance responses to ionizing radiation. In this study, the ability of gefitinib to modulate intratumoral oxygenation was evaluated in human EGFR-expressing A431 squamous cell carcinoma xenografts using in vivo small animal positron emission tomography (PET) imaging with the hypoxia marker [(18)F]fluoroazomycin arabinoside (FAZA) and by the immunohistochemical detection of hypoxia-induced adducts of the 2-nitroimidazole, pimonidazole. Serial noninvasive PET imaging of A431 xenografts showed a significant reduction in FAZA uptake following treatment with 75 mg/kg/d of gefitinib [tumor to background ratio, 6.1 +/- 1.0 (pretreatment) versus 2.3 +/- 0.6 (posttreatment); P = 0.0004]. Similarly, ex vivo quantitation of FAZA uptake showed significantly reduced FAZA uptake in established A431 xenografts treated with gefitinib compared with vehicle control (tumor to blood ratio for controls versus gefitinib, 8.0 +/- 3.0 versus 2.7 +/- 0.8; P = 0.007; or tumor to muscle ratio controls versus gefitinib, 8.6 +/- 2.8 versus 2.6 +/- 1.0; P = 0.002). The effect of gefitinib treatment seemed to be independent of tumor size. In addition, gefitinib treatment reduced pimonidazole-binding in A431 xenografts measured after 5 and 8 days of gefitinib treatment compared with baseline and with tumors treated with vehicle alone. A strong correlation was observed between pimonidazole binding and FAZA uptake. Together, these findings show that gefitinib reduces intratumoral hypoxia.

Widespread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women

Objective To use statistical parametric mapping to determine the extent of previously reported serotonin type 2A (5HT 2A) receptor binding potential (BP) increases in postmenopausal women following hormone therapy. Design Repeated measures positron emission tomography (PET) study. Setting Academic research environment. Patient(s) Five healthy, postmenopausal women. Intervention(s) Serial PET images of [ 18F]altanserin uptake were acquired to measure 5HT 2A receptor BP at menopausal baseline, following estradiol (E 2), and following combined E 2 + micronized progesterone (P 4). Main outcome measure(s) 5HT 2A receptor BP. Result(s) Combined E 2 + P 4 treatment was associated with significant increases in the 5HT 2A receptor BP increases in widespread areas of cerebral cortex. Treatment with E 2 alone was also associated with widespread cortical BP increases, although these changes reached statistical significance in fewer regions. The rate of [ 18F]altanserin metabolism was significantly decreased in the E 2 + P 4 condition relative to menopausal baseline, but this difference did not appear to correlate with changes in 5HT 2A receptor BP. Conclusion(s) Estradiol priming followed by combined E 2 + P 4 is associated with widespread increases in 5HT 2A receptor BP in the cerebral cortex, consistent with the E 2-associated increases in 5HT 2A receptor density previously observed in experimental animals.

Evaluation of a stereotactic frame for repositioning of the rat brain in serial positron emission tomography imaging studies

For serial imaging studies of the rat brain with positron emission tomography (PET), reproducible positioning of the head can facilitate spatial alignment of images and quantitative analysis. To achieve this aim, we constructed a plastic head frame and tested the positioning reproducibility on a high-resolution small-animal PET scanner, microPET. Two sets of ear bars, with tapers of either 18° (sharp) or 45° (blunt), were evaluated for their relative precision in securing the animal to the frame. For sequential positioning of an animal, average distances from the mean position of 0.51 mm (SD 0.41 mm) and 0.91 mm (SD 0.48 mm) were measured with the sharp and blunt ear bars, respectively. These results show that a rat brain can be reproducibly positioned using the frame, with a variation of position less than the spatial resolution of modern animal PET scanners. Brain regions of interest defined on one scan and copied across subsequent scans of a frame-repositioned animal resulted in an average coefficient of variation of 5.4% (SD 2.7%) using the sharp ear bars and 6.8% (SD 2.5%) using the blunt ear bars. This methodology has the potential to improve quantitative assessment for serial PET studies.

Muscle protein synthesis by positron-emission tomography with L-[methyl-11C]methionine in adult humans.

Existing methods for assessing protein synthetic rates (PSRs) in human skeletal muscle are invasive and do not readily provide information about individual muscle groups. Recent studies in canine skeletal muscle yielded PSRs similar to results of simultaneous stable isotope measurements using L-[1-13C, methyl-2H3]methionine, suggesting that positron-emission tomography (PET) with L-[methyl-11C]methionine could be used along with blood sampling and a kinetic model to provide a less invasive, regional assessment of PSR. We have extended and refined this method in an investigation with healthy volunteers studied in the postabsorptive state. They received approximately 25 mCi of L-[methyl-11C]methionine with serial PET imaging of the thighs and arterial blood sampling for a period of 90 min. Tissue and metabolite-corrected arterial blood time activity curves were fitted to a three-compartment model. PSR (nmol methionine.min-1.g muscle tissue-1) was calculated from the fitted parameter values and the plasma methionine concentrations, assuming equal rates of protein synthesis and degradation. Pooled mean PSR for the anterior and posterior sites was 0.50 +/- 0.040. When converted to a fractional synthesis rate for mixed proteins in muscle, assuming a protein-bound methionine content of muscle tissue, the value of 0.125 +/- 0.01%.h-1 compares well with estimates from direct tracer incorporation studies, which generally range from approximately 0.05 to 0.09%.h-1. We conclude that PET can be used to estimate skeletal muscle PSR in healthy human subjects and that it holds promise for future in vivo, noninvasive studies of the influences of physiological factors, pharmacological manipulations, and disease states on this important component of muscle protein turnover and balance.

Pharmacokinetics of [18F]trovafloxacin in healthy human subjects studied with positron emission tomography.

Tissue pharmacokinetics of trovafloxacin, a new broad-spectrum fluoroquinolone antimicrobial agent, were measured by positron emission tomography (PET) with [18F]trovafloxacin in 16 healthy volunteers (12 men and 4 women). Each subject received a single oral dose of trovafloxacin (200 mg) daily beginning 5 to 8 days before the PET measurements. Approximately 2 h after the final oral dose, the subject was positioned in the gantry of the PET camera, and 1 h later 10 to 20 mCi of [18F]trovafloxacin was infused intravenously over 1 to 2 min. Serial PET images and blood samples were collected for 6 to 8 h, starting at the initiation of the infusion. Drug concentrations were expressed as the percentage of injected dose per gram, and absolute concentrations were estimated by assuming complete absorption of the final oral dose. In most tissues, there was rapid accumulation of the radiolabeled drug, with high levels achieved within 10 min after tracer infusion. Peak concentrations of more than five times the MIC at which 90% of the isolates are inhibited (MIC90) for most members of Enterobacteriaceae and anaerobes (>10-fold for most organisms) were achieved in virtually all tissues, and the concentrations remained above this level for more than 6 to 8 h. Particularly high peak concentrations (micrograms per gram; mean +/- standard error of the mean [SEM]) were achieved in the liver (35.06 +/- 5.89), pancreas (32.36 +/- 20. 18), kidney (27.20 +/- 10.68), lung (22.51 +/- 7.11), and spleen (21. 77 +/- 11.33). Plateau concentrations (measured at 2 to 8 h; micrograms per gram; mean +/- SEM) were 3.25 +/- 0.43 in the myocardium, 7.23 +/- 0.95 in the lung, 11.29 +/- 0.75 in the liver, 9.50 +/- 2.72 in the pancreas, 4.74 +/- 0.54 in the spleen, 1.32 +/- 0.09 in the bowel, 4.42 +/- 0.32 in the kidney, 1.51 +/- 0.15 in the bone, 2.46 +/- 0.17 in the muscle, 4.94 +/- 1.17 in the prostate, and 3.27 +/- 0.49 in the uterus. In the brain, the concentrations (peak, approximately 2.63 +/- 1.49 microg/g; plateau, approximately 0.91 +/- 0.15 microg/g) exceeded the MIC90s for such common causes of central nervous system infections as Streptococcus pneumoniae (MIC90, <0.2 microg/ml), Neisseria meningitidis (MIC90, <0.008 microg/ml), and Haemophilus influenzae (MIC90, <0.03 microg/ml). These PET results suggest that trovafloxacin will be useful in the treatment of a broad range of infections at diverse anatomic sites.

Pharmacokinetics of [18F]fleroxacin in healthy human subjects studied by using positron emission tomography.

Positron emission tomography (PET) with [18F]fleroxacin was used to study the pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, in 12 healthy volunteers (9 men and 3 women). The subjects were infused with a standard therapeutic dose of fleroxacin (400 mg) supplemented with approximately 20 mCi of [18F]fleroxacin. Serial PET images were made and blood samples were collected for 8 h, starting at the initiation of the infusion. The subjects were then treated with unlabeled drug for 3 days (400 mg/day). On the fifth day, infusion of radiolabeled drug, PET imaging, and blood collection were repeated. In most organs, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion. Especially high peak concentrations (in micrograms per gram) were achieved in the kidney (> 34), liver (> 25), lung (> 20), myocardium (> 19), and spleen (> 18). Peak concentrations of drug more than two times the MIC for 90% of Enterobacteriaceae strains tested (> 10-fold for most organisms) were achieved in all tissues except the brain and remained above this level for more than 6 to 8 h. The plateau concentrations in tissues (2 to 8 h, in micrograms per gram +/- standard error of the mean) of drug were as follows: brain, 0.83 +/- 0.032; myocardium, 4.53 +/- 0.24; lung, 5.80 +/- 0.48; liver, 7.31 +/- 0.33; spleen, 6.00 +/- 0.47; bowel, 3.53 +/- 0.74; kidney, 8.85 +/- 0.64; bone, 2.87 +/- 0.29; muscle, 4.60 +/- 0.33; prostate, 4.65 +/- 0.48; uterus, 3.87 +/- 0.39; breast, 2.68 +/- 0.11; and blood, 2.35 +/- 0.09. Concentrations of fleroxacin in tissue were similar in males and females, before and after pretreatment with unlabeled drug.

Regional blood flow, oxidative metabolism, and glucose utilization in patients with recent myocardial infarction.

Metabolic imaging with positron emission tomography (PET) can detect tissue viability in clinical infarct regions. With appropriate tracer kinetic models and serial PET imaging, regional myocardial blood flow and rates of metabolism can now be quantified in patients with recent myocardial infarctions. Serial PET imaging with [13N]ammonia, [11C]acetate, and 18F-deoxyglucose was performed in 22 patients with recent infarctions to measure regional blood flow (in milliliters per gram per minute), glucose metabolism (in micromoles per gram per minute), and oxidative metabolism (in clearance rate per minute). Hypoperfused clinical infarct regions were classified as "PET mismatch" if 18F was increased relative to 13N activity or "PET match" if 13N and 18F activities were reduced concordantly. Blood flows differed significantly between normal, mismatch, and match segments (0.83 +/- 0.20, 0.57 +/- 0.20, and 0.32 +/- 0.12 mL.g-1.min-1, respectively). The relation between oxidative metabolism and blood flow was piecewise linear and differed significantly between PET mismatch and PET match. Oxidative metabolism was less severely reduced than blood flow in mismatch regions but but reduced in proportion to blood flow in match regions. There was considerable overlap of blood flows between both types of PET segments. Quantification of regional blood flow and substrate metabolism in postinfarction patients revealed alterations in the relation between substrate delivery and consumption demonstrated previously only in invasive animal experiments. The preserved oxidative metabolism in myocardium with PET mismatches may be ascribed to a regional increase in oxygen extraction. Such increase together with preserved glucose utilization may be the prerequisite for survival of ischemically injured myocardium.

Noninvasive quantification of regional myocardial blood flow and ammonia extraction fraction using nitrogen-13 ammonia and positron emission tomography.

This report describes the theoretical basis and a method to quantitate regional myocardial blood flow (RMBF) and ammonia extraction fraction (E) in man, noninvasively, with N-13 ammonia and positron emission tomography (PET). Two patients with hypertrophic cardiomyopathy, whose left ventricular (LV) walls were markedly thick, were employed in this study to avoid partial volume effects and cross contamination between LV walls and blood pool. RMBF and E were calculated from time-activity curves of myocardial tissue and left atrium derived from serial 6-second PET images of the heart. The time-activity curve of left atrium was used as an arterial input function. The results were RMBF = 67 +/- 4 ml/min/100 g, E = 80 +/- 13% and 65 +/- 10 ml/min/100 g, 81 +/- 16% for each patient. The validity of the present method was discussed.

Effects of substrate availability on myocardial C-11 palmitate kinetics by positron emission tomography in normal subjects and patients with ventricular dysfunction

The possibility of demonstrating noninvasively with C-11 palmitate and positron emission tomography (PET) changes in myocardial substrate metabolism in normal and diseased human myocardium in response to altered substrate availability in blood and disease-related abnormalities was examined in five normal volunteers and 16 patients with ventricular dysfunction. C-11 palmitate injection and serial PET imaging were performed after an overnight fast (control period) and again 2 hours later after oral glucose (50 gm). Myocardial C-11 time-activity curves from serial PET images revealed a biexponential clearance pattern. An early rapid phase, defined by relative size and clearance half-time, reflects C-11 palmitate oxidation and the late slow phase tracer deposition in the endogenous lipid pool. During the control period, the tracer fraction entering the early rapid phase averaged 47 ± 13% (SD) in normal subjects and 45 ± 12% in patients. Corresponding clearance half-times were 19 ± 7 and 20 ± 5 minutes, respectively. Heart rate and blood pressure remained unchanged after glucose, but plasma glucose levels rose by 72.5% in normal subjects and by 98.9% in patients, while free fatty acid levels fell by 72% and 42% ( p < 0.001), respectively. In normal subjects, the tracer fraction in the early rapid phase fell by 43% ( p < 0.005) and the clearance half-time increased by 46% ( p < 0.01). In patients, the response of C-11 palmitate tissue kinetics to glucose was variable. In nine patients, it was similar to that in normal subjects while in the other seven patients a “paradoxic” response occurred. The tracer fraction entering the rapid clearance phase increased after glucose by 30% ( p < 0.05) associated with a 36% ( p < 0.05) decline in clearance half-times. The paradoxic response was unrelated to disease etiology or plasma substrate levels but occurred mostly in left ventricles with more severely depressed function. Thus, PET and C-11 palmitate allow the noninvasive demonstration of the known response of substrate metabolism of the human heart to altered substrate availability. Glucose administration in fasted humans serves as a provocative test of substrate regulation which can be abnormal in myocardial disease and can be demonstrated noninvasively.