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Quantification of myocardial beta-adrenoceptor density (B-max) is of interest in cardiac diseases in which altered function of the sympathetic nervous system is thought to play a pathophysiological role. PET provides an unrivaled means of taking regional measurements of cardiac microcirculatory function, tissue metabolism and autonomic nervous system activity. Measurements in small regional areas may be biased because of increased noise levels. This study examined the parametric polar map approach for the regional quantification of B-max. Methods: Dynamic PE-T with parametric polar map imaging was performed in 10 healthy volunteers and 4 patients with hypertrophic cardiomyopathy using (S)-[C-11]-(4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzidimazole-2)-o n hydrochloride (CGP)-12177 and a double-injection protocol. Time-activity curves were corrected for partial volume, spill-over and wall motion effects. The mean B-max of the left ventricle was calculated in two ways. First, the average time-activity curve of all segments, having the highest achievable signal-to-noise ratio, was used to calculate B-max(mTAC) (the myocardial beta-adrenoceptor density of the left ventricle calculated using the average time-activity curve). The bias in B-max(mTAC) introduced by noise is minimal. Second, an estimate of whole-heart receptor density was calculated using the polar map method by averaging the values of B-max obtained for 576 individual segments. In these calculations, three different filters (3 x 5, 3 x 9 and 3 x 13 segments) were used to smooth the time-activity curves before calculating B-max. Mean values of whole-left-ventricular receptor density obtained by averaging regional values using the different filters (B-max(PMF1/2/3)) were compared with B-max(mTAC) to assess bias introduced by the polar map approach. Segments with a calculated B-max outside the range 0.1-50 pmol/g were considered unreliable and were excluded from the analysis. Results: The differences between the two methods of calculating B-max were small (7.8%, 4.8% and 3.2%, with the three filters, respectively). Reliable results were obtained in >95% of the segments and in 9 volunteers and all 4 patients. Conclusion: When using PET for the quantification of beta-adrenoceptor density, the regional variation in B-max can be reliably assessed using the parametric polar map approach.

1 Imaging of P-glycoprotein (P-gp) function in the blood-brain barrier (BBB) may support evelopment of strategies, which will improve drug delivery to the brain. [C-11] verapamil has been developed as a positron emission tomography ( PET) tracer, to image P-gp function in vivo. Ideally, for the purpose of brain imaging, tracers should have a log P between 0.9 and 2.5. The beta-receptor antagonist carvedilol is a P-gp substrate with a log P = 2.0, and can be labeled with [C-11]. The aim of this study was to determine whether the P-gp substrate [C-11] carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB. 2 Cellular [C-11] carvedilol accumulation in GLC(4), GLC(4)/P-gp, and GLC(4)/Adr cells increased three-fold in the GLC(4)/P-gp cells after pretreatment with cyclosporin A (CsA) whereas no effect of MK571 could be determined in the GLC4/Adr cells. 3 Ex vivo [C-11] carvedilol biodistribution studies showed that [C-11] carvedilol uptake in the brain was increased by CsA. [C-11] carvedilol uptake in other organs was not affected by CsA. 4 Autoradiography studies of rat brains showed that [ C-11] carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [C-11] carvedilol uptake. 5 In vivo PET experiments were performed with and without P-gp modulation by CsA. P-gp mediated transport was quantified by Logan analysis of the PET data, calculating the distribution volume (DV) of [C-11] carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [C-11] carvedilol is not trapped in the brain. Brain DV of [C-11] carvedilol showed a dose-dependent increase of maximal three-fold after CsA pretreatment. Above 15 mg kg(-1), no change in DV was found. Compared to [C-11] verapamil less CsA was needed to reach maximal DV, suggesting that [C-11] carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.

The purpose of this study was to appraise the value of PET in the assessment of the effect of supposedly proangiogenic new therapies such as gene therapy with vascular endothelial growth factor (VEGF) gene and endomyocardial laser therapy. Methods: Thirty-five patients with end-stage coronary artery disease and class III (Canadian Cardiovascular Society) angina were included. Myocardial ischemia was evaluated with dipyridamole PET scanning and exercise tolerance with bicycle ergometry. Ten patients were treated with naked plasmid DNA encoding for human VEGF(165) (VEGF) and 12 patients were treated with laser therapy (direct myocardial revascularization [DMR]) using an electromechanical mapping system. Thirteen patients were treated with standard medical therapy (control). Results: In both active treatment groups, angina was reduced in most subjects, except in 2 VEGF and 5 DMR patients. In the control group, no improvement in anginal classification was found, except in 3 subjects. On the PET scan, solely in the VEGF group, the stress perfusion was significantly improved (from 57 +/- 33 to 81 +/- 55 mL/min/100 g; P = 0.031). Furthermore, in the VEGF group, the number of ischemic segments was reduced from 274 +/- 41 to 234 +/- 48 segments (P = 0.004) but not in the DMR group (from 209 +/- 43 to 215 +/- 52 segments) or in the control group (from 218 +/- 18 to 213 +/- 28 segments). Bicycle exercise duration showed slight nonsignificant changes in the VEGF group (from 3.6 +/- 2.0 to 4.6 +/- 2.1 min), in the DMR group (from 5.1 +/- 1.5 to 4.7 +/- 1.3 min), and in the control group (from 3.3 +/- 1.8 to 3.5 +/- 2.3 min). Conclusion: PET showed that intramyocardial gene therapy with the human VEGF(165) gene in contrast to laser DMR treatment effectively reduces myocardial ischemia.

The aim of this study was to compare left ventricular (LV) volumes and regional wall motion determined by PET with those determined by the reference technique, cardiovascular MRI. Methods: LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were measured and regional wall motion was scored in 38 patients with chronic coronary artery disease by both gated F-18-FDG PET and MRI. A 9-segment model was used for PET and MRI to assess regional wall motion. Results: Good correlations were observed between MRI and gated PET for all parameters (r values ranging from 0.91 to 0.96). With PET, there was a significant but small underestimation of LVEDV and LVEF. Mean+/-SD LVEDV, LVESV, and LVEF for MRI were 131+/-57 mL, 91+/-12 mL, and 33%+/-12%, respectively, and those for gated PET were 117+/-56 mL, 85+/-51 mL, and 30%+/-11%, respectively. For regional wall motion, an agreement of 85% was found, with a kappa-statistic of 0.79 (95% confidence interval, 0.70-0.89; SE, 0.049). Conclusion: LV volumes, LVEF, and regional wall motion can be assessed with gated F-18-FDG PET and correlate well with these parameters assessed by MRI.

PET with F-18-FDG is used for detection and staging of thoracic cancer; however, more specific PET radiopharmaceuticals would be welcome. C-11-labeled choline (CHOL) is a new radiopharmaceutical potentially useful for tumor imaging, since it is incorporated into cell membranes as phosphatidylcholine. The aim of this study was to investigate whether C-11-CHOL PET has advantages over F-18-FDG PET in patients with thoracic cancer. Methods: We evaluated 17 patients with thoracic cancer both with C-CHOL PET and F-18-FDG PET. After transmission scanning, C-11-CHOL was injected intravenously, and whole-body scanning was started after 5 min. Immediately thereafter, F-18-FDG was injected intravenously, followed after 90 min by interleaved attenuation-corrected whole-body scanning. Scans were performed from crown to femur. Visual and quantitative (standardized uptake value) analyses of C-11-CHOL PET and F-18-FDG PET were performed and compared with results of traditional staging and follow-up. Results: The most prominent features of normal C-11-CHOL distribution were high uptake in liver, renal cortex, and salivary glands. Except for some uptake in choroid plexus and pituitary gland, brain uptake was negligible. All primary thoracic tumors were detected with C-11-CHOL PET and F-18-FDG PET. Both C-11-CHOL PET and F-18-FDG PET correctly identified all 16 patients with lymph node involvement. However, in a lesion-to-lesion analysis, C-11-CHOL PET detected only 29 of 43 metastatic lymph nodes, whereas F-18-FDG PET detected 41 of 43. C-11-CHOL PET detected fewer intrapulmonary and pleural metastases than F-18-FDG PET (27/47 vs. 46/47). More brain metastases were detected with C-11-CHOL PET (23/23) than with F-18-FDG PET (3/23). For primary tumors, the median (range) standard uptake values of C-11-CHOL and F-18-FDG were 1.68 (0.98-3.22) and 4.22 (1.40-8.26), respectively (P = 0.001). Conclusion: C-11-CHOL PET can be used to visualize thoracic cancers. Although detection of lymph node metastases with C-11-CHOL PET was inferior compared with F-18-FDG PET, the detection of brain metastases was superior.

Drug resistance is a major cause of chemotherapy failure in cancer treatment, One reason is the overexpression of the drug efflux pump P-glycoprotein (P-gp), involved in multidrug resistance (MDR), In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P-gp function was measured in vivo with positron emission tomography (PET) and [C-11]verapamil as radiolabeled P-gp substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC(4)) and its P-gp-overexpressing subline (GLC(4)/P-gp). For validation, in vitro and biodistribution studies with [C-11]daunorubicin and [C-11]verapamil were performed. [C-11]Daunorubicin and [C-11]verapamil accumulation were higher in GLC(4) than in GLC(4)/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC(4)/P-gp. Biodistribution studies showed 159% and 185% higher levels of [C-11]daunorubicin and [C-11]verapamil, respectively, in GLC(4) than in GLC(4)/P-gp tumors. After cyclosporin A, [C-11]daunorubicin and [C-11]verapamil content in the GLC(4)/P-gp tumor was raised to the level of GLC(4) tumors. PET measurements demonstrated a lower [C-11]verapamil content in GLC(4)/P-gp tumors compared with GLC(4) tumors. Pretreatment with cyclosporin A increased [C-11]verapamil levels in GLC(4)/P-gp tumors (184%) and in brains (1280%). This pharmacokinetic effect was clearly visualized with PET. These results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P-gp modulator to MDR drugs.

Heterogeneity of left ventricular myocardial perfusion is an important clinical characteristic. Different aspects of this heterogeneity were analyzed. Methods: The coefficient of variation (v), characterizing heterogeneity, was modeled as a function of the number of segments (n), characterizing spatial resolution of the measurement, using two independent pairs of mutually dependent parameters: the first pair describes v as a power function of n, and the second pair adds a correction for n small. n was Varied by joining equal numbers of neighboring segments. Local similarity of the perfusion was characterized by the correlation between the perfusions of neighboring segments, Genesis of the perfusion distribution was modeled by repeated asymmetric subdivision of the perfusion into a volume among two equal subvolumes. These analyses were applied to study the differences between 16 syndrome X patients and 16 age- and sex-matched healthy volunteers using N-13-ammonia parametric PET perfusion data with a spatial resolution of 480 segments. Results: The heterogeneity of patients is higher for the whole range of spatial resolutions considered (2 less than or equal to n less than or equal to 480; for n = 480, v = 0.22 +/- 0.03 and 0.18 +/- 0.02; p 0.1), For both groups of subjects there is a significant positive local correlation for distances up to 30 segments. This correlation is a formal description of the patchy nature of the perfusion distribution. Conclusion: When comparing values of v, these should be based on the same value of n. The model makes it possible to calculate v for all values of n 480. Mean perfusion together with the two pairs of parameters are necessary and sufficient to describe all aspects of the perfusion distribution. For n small, heterogeneity estimation is less reliable. Patients have a higher heterogeneity because their perfusion distribution is more asymmetrical from the third to the seventh generation of subdivision (8 less than or equal to n less than or equal to 128). Therefore, a spatial resolution of n greater than or equal to 128 is recommended for parametric imaging of perfusion with PET. Patients have only a very slightly more patchy distribution than volunteers. The differences in perfusion between areas with low perfusion and areas with high perfusion is larger in patients.

1 Homozygously mdr1a gene disrupted mice (mdr1a(-/-) mice) and wild type mice (mdr1a(+/+) mice) were used to develop a method for P-glycoprotein (P-gp) function imaging non-invasively and to study the effect of a P-gp reversal agent on its function in vivo. 2 [C-11]verapamil (0.1 mg/kg) was administered and the changes in tissue concentrations were determined ex vivo by organ extirpation and in viva with PET. To block P-gp function, cyclosporin A was administered. 3 Biodistribution studies revealed 9.5-fold (P 4 Positron camera data showed lower [C-11]verapamil levels in the brain of mdr1a(+/+) mice compared to those in mdr1a(-/-) mice. [C-11]verapamil accumulation in the brain of mdr1a(+/+) mice was increased by cyclosporin A to levels comparable with those in mdr1a(-/-) mice, indicating that reversal of P-gp mediated efflux can be monitored by PET. 5 We conclude that cyclosporin A can fully block the P-gp function in the blood brain barrier and the testes and that PET enables the in viva measurement of P-gp function and reversal of its function noninvasively.

Although the brain plays a crucial role in the control of micturition, little is known about the structures involved. Identification of these areas is important because their dysfunction is thought to cause urge incontinence, a major problem in the elderly. In the cat, three areas in the brainstem and diencephalon are specifically implicated in the control of micturition: the dorsomedial pontine tegmentum, the periaqueductal grey, and the preoptic area of the hypothalamus. PET scans were used to test whether these areas are also involved in human micturition. Seventeen right-handed male volunteers were scanned during the following four conditions: (i) 15 min prior to micturition during urine withholding; (ii) during micturition; (iii) 15 min after micturition; (iv) 30 min after micturition. Ten of the 17 volunteers were able to micturate during scanning. Micturition was associated with increased blood flow in the right dorsomedial pontine tegmentum, the periaqueductal grey, the hypothalamus and the right inferior frontal gyrus. Decreased blood flow was found in the right anterior cingulate gyrus when urine was withheld. The other seven volunteers were not able to micturate during scanning, although they had a full bladder and tried vigorously to do so. In this group, during these unsuccessful attempts to micturate, increased blood pow was Sound in the right ventral pontine tegmentum, which corresponds with the hypothesis, formulated from results in cats, that this area controls the motor neurons of the pelvic poor Increased blood pow was also found in the right inferior frontal gyrus during unsuccessful attempts at micturition, and decreased blood pow in the right anterior cingulate gyrus was found during the withholding of urine. The results suggest that, as that of the cat, the human brainstem contains specific nuclei responsible for the control of micturition, and that the cortical and pontine micturition sites are predominantly on the right side.

The isotopes Co-55 and Co-57 have been evaluated for PET and SPECT imaging in several clinical brain studies. For clinical application of cobalt, it is important to know the delivered radiation dose. The biodistribution of Co-55 in both rat and humans after intravenous (bolus)-administration was studied. Based on pharmacokinetic data, radiation dose calculations according to the MIRD system are presented, By combining present measurements with literature data on (CoCl2)-Co-60, the radiation dose delivered by (CoCl2)-Co-56 (T-1/2 78.8 days) and (CoCl2)-Co-57 (T-1/2 = 270 days) could be assessed. Methods: Whole-body Co-PET was performed in two healthy volunteers and one rat after intravenous injection of 37 and 3.7 MBq (1 resp, 0.1 mCl) Co-55, respectively. Blood samples were withdrawn during 300 min in humans. In seven rats the Co-55-biodistribution was determined by postmortem analysis. The residence time of the liver (critical organ) was determined in rats and humans. Blood partition-data of Co-55 were assessed resulting in basic pharmacokinetic data in humans. Based on these kinetic data, radiation dose was calculated using the MIRD protocol. Results: In both the humans and the rat, the liver and bladder retained the highest fractions of Co-55 (about 50% resp. 40% of the administered dose), The liver residence time in humans was 8.6 hr. The free fraction Co-55 in the human plasma was at maximum 12%. The total-body mean transit time was 152 min. The volume of the central compartment = 2.8 liter and the steady-state distribution volume = 48 liter. Conclusion: From these results, according to the WHO recommendations for class II studies, 22.2 MBq (0.6 mCi) Co-55 and 14.8 MBq (0.4 mCi) Co-57 (excluding any radionuclide contamination) can be used.

We investigated FDG-PET in patients undergoing hyperthermic isolated limb perfusion (HILP) with rTNF-alpha, rIFN-gamma and melphalan for locally advanced soft-tissue sarcoma of the extremities. Methods: Twenty patients (11 women, 9 men; aged 18-80 yr, mean age 49 yr) were studied, FDG-PET studies were performed before, 2 and 8 wk after HILP. After the final PET study, the tumor was resected and pathologically graded, Patients with pathologically complete response (pCR) showed no viable tumor after treatment, Those with pathologically partial response (pPR) showed various amounts of viable tumor in the resected specimens. Results Seven patients showed a pCR (35%) and 12 patients showed a pPR (60%). In one patient, pathological examination was not performed (5%). The pre-perfusion glucose consumption in the pCR group was significantly higher than in the pPR group (p

The posterolateral defect is a common artifact seen when static N-13-ammonia imaging with PET is used to assess myocardial perfusion. The aim of this study was to compare dynamic and static N-13-ammonia PET and to obtain more insight into the cause of the posterolateral defect. Methods: Dynamic N-13-ammonia PET was performed in 19 healthy nonsmoking volunteers at rest. Perfusion was assessed in the early phase of the study using a curve fit method over the first 90 sec. Nitrogen-13 accumulation (static PET) was assessed 4 to 8 min after injection. Each study was normalized to a mean of 100. The average distribution of normalized perfusion and activity was calculated in 24 segments. Heterogeneity of both activity and perfusion distribution were assessed and the activity distribution was compared with perfusion distribution. Results: Perfusion distribution was homogeneous, with the exception of the inferior and apical regions. Activity distribution was inhomogeneous, with a lower activity in the posterolateral and apical regions. In the whole left ventricle, significant differences in distribution were found between static and dynamic imaging. Conclusion: Perfusion distribution was significantly different on dynamic images compared to static images. The posterolateral defect was not found on dynamic images. The posterolateral defect and other inhomogeneities in activity distribution are caused by tracer-dependent features, probably a redistribution of metabolites of N-13-ammonia.

Most efficacy studies of cardiac PET in demonstrating myocardial ischemia and viability have been performed using one or more transversal static images of the heart. In contrast, in this paper we describe a method of functional imaging of the complete left ventricular myocardium for perfusion with nitrogen-13-ammonia, both at rest and during a dipyridamol stress test, and of glucose metabolism with F-18-fluorodeoxyglucose ((18)FDG). Methods: This was performed by using the data of each of 48 radial segments of 10 short-axis images as tissue data and LV cavity data of three basal planes as blood pool data. The study describes the results of 19 normal volunteers and 36 patients with coronary artery disease. From the data of the normal volunteers a 95% normal confidence interval was calculated for each imaging modality. These intervals were then used to describe the patient data as normal, ischemic or infarcted. Results: The results of analysis of the parametric images was compared with the results of static analysis of the same patient data and found to be less dependant on the detection threshold used. Conclusion: The described method enables the routine application of functional PET imaging of the total myocardium by the semi-automatic construction of parametric flow and metabolism polar maps. It thus provides an increased performance in the diagnosis, quantification and localization of myocardial ischemia and viability over conventional PET imaging.