Comparison of [(18)F]altanserin and [(18)F]deuteroaltanserin for PET imaging of serotonin(2A) receptors in baboon brain: pharmacological studies.

The regional distribution in brain, distribution volumes, and pharmacological specificity of the PET 5-HT(2A) receptor radiotracer [(18)F]deuteroaltanserin were evaluated and compared to those of its non-deuterated derivative [(18)F]altanserin. Both radiotracers were administered to baboons by bolus plus constant infusion and PET images were acquired up to 8 h. The time-activity curves for both tracers stabilized between 4 and 6 h. The ratio of total and free parent to metabolites was not significantly different between radiotracers; nevertheless, total cortical R(T) (equilibrium ratio of specific to nondisplaceable brain uptake) was significantly higher (34-78%) for [(18)F]deuteroaltanserin than for [(18)F]altanserin. In contrast, the binding potential (Bmax/K(D)) was similar between radiotracers. [(18)F]Deuteroaltanserin cortical activity was displaced by the 5-HT(2A) receptor antagonist SR 46349B but was not altered by changes in endogenous 5-HT induced by fenfluramine. These findings suggest that [(18)F]deuteroaltanserin is essentially equivalent to [(18)F]altanserin for 5-HT(2A) receptor imaging in the baboon.

Reproducibility of in vivo brain measures of 5-HT2A receptors with PET and.

The test/retest reproducibility of brain measures of 5-HT2A receptors with positron emission tomography (PET) and [18F]deuteroaltanserin was examined in a group of eight healthy human subjects. PET measures of 5-HT2A receptors were obtained under an equilibrium paradigm, with a 40-min PET acquisition starting approximately at 300 min (308+/-11 min) after bolus plus constant infusion of the radiotracer. Three brain outcome measures were obtained at equilibrium, V(3) (ratio of specific brain uptake to free parent plasma concentration of radiotracer), V(3)' (ratio of specific brain uptake to total parent plasma concentration) and RT (ratio of specific to non-displaceable brain uptakes). V(3)' and RT had high test/retest reproducibility, as measured by mean intra-subject% change for cortical brain areas of 14.1 and 11.0%, respectively. They also had high reliability, as measured by mean intra-class correlation coefficients (ICC) for cortical brain areas of 0.86 and 0.88, respectively. V(3) had low test/retest reproducibility, due to high variability in the measures of free parent tracer in plasma. This study supports the feasibility of equilibrium imaging of 5-HT2A receptors with PET and [18F]deuteroaltanserin. The equilibrium imaging method with [18F]deuteroaltanserin allows a single acquisition and blood measurement to provide an image whose pixel values equal a receptor volume of distribution. Since the single image pixel values are proportional to receptor densities, the images can be used in pixel-by-pixel statistical methods, such as SPM, to assess the distribution and density of 5-HT2A receptors in neuropsychiatric disorders.

Gender differences in cognitive and neural correlates of remembrance of emotional words.

Studies suggest that men and women have important differences in specific cognitive functions. Men show superior spatial memory and women demonstrate superior verbal memory, and women rely on emotional content to a greater degree in the processing of information. In spite of extensive research in neural correlates of human cognition, little is known about possible gender differences or the role of emotional content in the mediation of cognition. Two sets of lists of word pairs were developed, one with neutral (e.g., school-grocery) and the other with emotional (e.g., mutilate-beat) content. Male and female subjects were asked to rate emotions related to the words on several dimensions (e.g., nervous, fearful, happy). In a second experiment, men and women underwent positron emission tomographic (PET) measurement of brain blood flow during retrieval of word pairs. Words in the "emotional" category were rated more highly on the emotional dimensions, and women rated them as having more emotional impact than did the men. During retrieval of emotional words (but not neutral words) there was a different pattern of activation among the women compared with the men, with greater activation in bilateral posterior hippocampus and cerebellum, and decreased activity in medial prefrontal cortex, which are brain areas previously implicated in emotion. There were no significant differences in retrieval of emotional versus neutral words, or in differences in memory performance between men and women. The findings suggest differences in cognitive appraisal and involvement of a broader network of brain regions mediating emotion during remembrance of emotional words in women compared with men.

Myocardial blood-flow response during mental stress in patients with coronary artery disease.

Positron emission tomography was used to quantify changes in myocardial blood flow during mental stress in patients with and without coronary artery disease. Blunted augmentation of myocardial blood flow during mental stress was observed in regions without significant epicardial stenosis.

Persistent changes in myocardial glucose metabolism in vivo during reperfusion of a limited-duration coronary occlusion.

BACKGROUND: Rapid reperfusion of an occluded coronary artery salvages regional mechanical function, but this benefit may not be realized for hours or days because of postischemic stunning. Recovery from stunning is incompletely understood but may involve adaptive changes in heart glucose metabolism. METHODS AND RESULTS: To examine whether reversible coronary occlusion produces sustained changes in regional glucose metabolism in vivo, we performed a 20-minute left coronary artery occlusion followed by 24 hours of open-artery reperfusion in intact rats. Coronary occlusion produced stunning of the anterolateral left ventricle that resolved over 24 hours. When examined at 24 hours, reperfused regions were fully contractile and viable by vital staining and microscopy but demonstrated 25% reduction in blood flow and 50% increased uptake of circulating glucose, as estimated by in vivo [(13)N]NH(3) and [(18)F]fluorodeoxyglucose (FDG) tracer uptake. Reperfused regions had largely inactive glycogen synthase, low rates of glycogen synthesis, and persistent 50% glycogen depletion but increased flux of plasma [1-(13)C]glucose into myocardial [3-(13)C]alanine, indicating preferential shunting of imported glucose away from storage and into glycolysis. CONCLUSIONS: Sustained increases in regional glycolytic consumption of circulating glucose occur during reperfusion of a limited-duration coronary occlusion. This suggests a role for glycolytic ATP in the recovery from postischemic stunning in vivo. Furthermore, [(13)N]NH(3) /FDG regional mismatch may constitute a clinically accessible late metabolic signature of regional myocardial ischemia.

PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin.

UNLABELLED: [18F]altanserin has been used to label serotonin 5-HT2A receptors, which are believed to be important in the pathophysiology of schizophrenia and depression. The purpose of this study was to test the feasibility of a constant infusion paradigm for equilibrium modeling of [18F]altanserin with PET. Kinetic modeling with [18F]altanserin may be hampered by the presence of lipophilic radiometabolites observed in plasma after intravenous administration. METHODS: Eight healthy volunteers were injected with [18F]altanserin as a bolus (208+/-9 MBq [5.62+/-0.25 mCi]) plus constant infusion (65+/-3 MBq/h [1.76+/-0.08 mCi/h]) ranging from 555 to 626 min (615+/-24 min) after injection. PET acquisitions (10-20 min) and venous blood sampling were performed every 30-60 min throughout the infusion period. RESULTS: Linear regression analysis revealed that time-activity curves for both brain activity and plasma [18F]altanserin and metabolite concentrations stabilized after about 6 h. This permitted equilibrium modeling and estimation of V3' (ratio of specific uptake [cortical-cerebellar] to total plasma parent concentration after 6 h). Values of V3' ranged from 1.57+/-0.38 for anterior cingulate cortex to 1.02+/-0.39 for frontal cortex. The binding potential V3 (ratio of specific uptake to free plasma parent concentration after 6 h, using group mean f1) was also calculated and ranged from 169+/-41 for anterior cingulate cortex to 110+/-42 for frontal cortex. From 6 h onward, the rate of change for V3' and V3 was only 1.11+/-1.69 %/h. CONCLUSION: These results demonstrate the feasibility of equilibrium imaging with [18F]altanserin over more than 5 radioactive half-lives and suggest a method to overcome difficulties associated with lipophilic radiolabeled metabolites. The stability in V3 and V3' once equilibrium is achieved suggests that a single PET acquisition obtained at 6 h may provide a reasonable measure of 5-HT2A receptor density.

Kinetic modeling of benzodiazepine receptor binding with PET and high specific activity [(11)C]Iomazenil in healthy human subjects.

Quantitation of the PET benzodiazepine receptor antagonist, [(11)C]Iomazenil, using low specific activity radioligand was recently described. The purpose of this study was to quantitate benzodiazepine receptor binding in human subjects using PET and high specific activity [(11)C]Iomazenil. Six healthy human subjects underwent PET imaging following a bolus injection of high specific activity (>100 Ci/mmol) [(11)C]iomazenil. Arterial samples were collected at multiple time points after injection for measurement of unmetabolized total and nonprotein-bound parent compound in plasma. Time activity curves of radioligand concentration in brain and plasma were analyzed using two and three compartment model. Kinetic rate constants of transfer of radioligand between plasma, nonspecifically bound brain tissue, and specifically bound brain tissue compartments were fitted to the model. Values for fitted kinetic rate constants were used in the calculation of measures of benzodiazepine receptor binding, including binding potential (the ratio of receptor density to affinity), and product of BP and the fraction of free nonprotein-bound parent compound (V(3)'). Use of the three compartment model improved the goodness of fit in comparison to the two compartment model. Values for kinetic rate constants and measures of benzodiazepine receptor binding, including BP and V(3)', were similar to results obtained with the SPECT radioligand [(123)I]iomazenil, and a prior report with low specific activity [(11)C]Iomazenil. Kinetic modeling using the three compartment model with PET and high specific activity [(11)C]Iomazenil provides a reliable measure of benzodiazepine receptor binding. Synapse 35:68-77, 2000. Published 2000 Wiley-Liss, Inc.

Quantitation of benzodiazepine receptor binding with PET [11C]iomazenil and SPECT [123I]iomazenil: preliminary results of a direct comparison in healthy human subjects.

Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [11C]iomazenil and [123I]iomazenil, respectively. All subjects were administered a single bolus of high specific activity iomazenil labeled with 11C or 123I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP = Bmax/Kd) and product of BP and the fraction of free non-protein-bound parent compound (V3'). Mean values for V3' in PET and SPECT were as follows: temporal cortex 23+/-5 and 22+/-3 ml/g, frontal cortex23+/-6 and 22+/-3 ml/g, occipital cortex 28+/-3 and 31+/-5 ml/g, and striatum 4+/-4 and 7+/-4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.

A complete remote-control system for reliable preparation of [18F]altanserin.

A complete remote control system was constructed for production of the PET 5-HT2A ligand [18F]altanserin by nitro-for-fluoro exchange. Comparing with published methods, the key features include (1) conducting azeotropic distillation and nucleophilic displacement in an open vessel heated by a commercial microwave oven; (2) purifying the product by a single HPLC procedure and (3) removing HPLC solvent by solid phase extraction. The preparation took 114 min with 23% yield and high quality.

Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) show a reliable increase in PTSD symptoms and physiological reactivity following exposure to traumatic pictures and sounds. In this study neural correlates of exposure to traumatic pictures and sounds were measured in PTSD. METHODS: Positron emission tomography and H2[15O] were used to measure cerebral blood flow during exposure to combat-related and neutral pictures and sounds in Vietnam combat veterans with and without PTSD. RESULTS: Exposure to traumatic material in PTSD (but not non-PTSD) subjects resulted in a decrease in blood flow in medial prefrontal cortex (area 25), an area postulated to play a role in emotion through inhibition of amygdala responsiveness. Non-PTSD subjects activated anterior cingulate (area 24) to a greater degree than PTSD patients. There were also differences in cerebral blood flow response in areas involved in memory and visuospatial processing (and by extension response to threat), including posterior cingulate (area 23), precentral (motor) and inferior parietal cortex, and lingual gyrus. There was a pattern of increases in PTSD and decreases in non-PTSD subjects in these areas. CONCLUSIONS: The findings suggest that functional alternations in specific cortical and subcortical brain areas involved in memory, visuospatial processing, and emotion underlie the symptoms of patients with PTSD.

Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease.

The central nervous system (CNS) effects of mental stress in patients with coronary artery disease (CAD) are unexplored. The present study used positron emission tomography (PET) to measure brain correlates of mental stress induced by an arithmetic serial subtraction task in CAD and healthy subjects. Mental stress resulted in hyperactivation in CAD patients compared with healthy subjects in several brain areas including the left parietal cortex [angular gyrus/parallel sulcus (area 39)], left anterior cingulate (area 32), right visual association cortex (area 18), left fusiform gyrus, and cerebellum. These same regions were activated within the CAD patient group during mental stress versus control conditions. In the group of healthy subjects, activation was significant only in the left inferior frontal gyrus during mental stress compared with counting control. Decreases in blood flow also were produced by mental stress in CAD versus healthy subjects in right thalamus (lateral dorsal, lateral posterior), right superior frontal gyrus (areas 32, 24, and 10), and right middle temporal gyrus (area 21) (in the region of the auditory association cortex). Of particular interest, a subgroup of CAD patients that developed painless myocardial ischemia during mental stress had hyperactivation in the left hippocampus and inferior parietal lobule (area 40), left middle (area 10) and superior frontal gyrus (area 8), temporal pole, and visual association cortex (area 18), and a concomitant decrease in activation observed in the anterior cingulate bilaterally, right middle and superior frontal gyri, and right visual association cortex (area 18) compared with CAD patients without myocardial ischemia. These findings demonstrate an exaggerated cerebral cortical response and exaggerated asymmetry to mental stress in individuals with CAD.

Effects of mental stress on left ventricular and peripheral vascular performance in patients with coronary artery disease.

OBJECTIVES: We sought to investigate the mechanism of a mental stress-induced fall in left ventricular ejection fraction (LVEF) in patients with coronary artery disease. BACKGROUND: Mental stress induces a fall in LVEF in a significant proportion of patients with coronary artery disease. This is accompanied by an increase in heart rate, blood pressure and rate-pressure product. Whether the mental stress-induced fall in LVEF is due to myocardial ischemia, altered loading conditions or a combination of both is not clear. METHODS: Left ventricular (LV) function was studied noninvasively by serial equilibrium radionuclide angiocardiography and simultaneous measurement of peak power, a relatively afterload-independent index of LV contractility, in 21 patients with coronary artery disease (17 men, 4 women) and 9 normal subjects (6 men, 3 women) at baseline, during mental stress and during exercise. Peripheral vascular resistance (PVR), cardiac output (CO), arterial and end-systolic ventricular elastance (Ea, Ees,) and ventriculoarterial coupling (V/AC) were also calculated. Patients underwent two types of mental stress-mental arithmetic and anger recall-as well as symptom-limited semisupine bicycle exercise. RESULTS: Nine patients (43%) had an absolute fall in LVEF of > or = 5% (Group I) in response to at least one of the mental stressors, whereas the remaining patients did not (Group II). Group I and Group II patients were similar in terms of baseline characteristics. Both groups showed a significant but comparable increase in systolic blood pressure (15+/-7 vs. 9+/-10 mm Hg, p=0.12) and a slight increase in heart rate (7+/-4 vs. 8+/-7 beats/min, p=0.6) and a comparable increase in rate-pressure product (2.2+/-0.9 vs. 1.9+/-1.2 beats/min x mm Hg, p=0.6) with mental stress. However, PVR increased in Group I and decreased in Group II (252+/-205 vs. -42+/-230 dynes x s x cm(-5), p=0.006), and CO decreased in Group I and increased in Group II (-0.2+/-0.4 vs. 0.6+/-0.7 liters/min, p=0.02) with mental stress. There was no difference in the change in peak power (p=0.4) with mental stress. With exercise, an increase in systolic blood pressure, heart rate, rate-pressure product and CO and a fall in PVR were similar in both groups. Of the two mental stressors, anger recall resulted in a greater fall in LVEF and a greater increase in diastolic blood pressure. Exercise resulted in a fall in LVEF in 7 patients (33%). However, exercise-induced changes in LVEF and hemodynamic variables were not predictive of mental stress-induced changes in LVEF and hemodynamic variables. Conclusions. Abnormal PVR and Ea responses to mental stress and exercise are observed in patients with a mental stress-induced fall in LVEF. Peripheral vasoconstrictive responses to mental stress contribute significantly toward a mental stress-induced fall in LVEF.

Effect of hyperinsulinemia on myocardial fluorine-18-FDG uptake.

UNLABELLED: This study was performed to evaluate the effect of insulin on myocardial kinetics of 18F-fluorodeoxyglucose (FDG) and glucose in patients with ischemic heart disease. METHODS: Twelve male patients (age range 54-79 yr; mean age 69 +/- 8 yr) were studied during the fasting awake state. Patients with diabetes and previous myocardial infarction of the left anterior descending vascular bed were excluded from the study. Patients were injected with a 185-MBq (5-mCi) bolus of FDG during arterial and coronary sinus catheterization. Thirty minutes after FDG injection, paired basal arterial and coronary sinus blood samples were taken for the measurement of FDG and glucose uptake. Thereafter, a primed (100 mU x m(-2) x min(-1) for 10 min) continuous (50 mU x m(-2) x min(-1) infusion of insulin was administered for 60 min using the euglycemic clamp technique, and blood samples were repeated. Blood samples also were taken periodically for the measurement of arterial free fatty acids and insulin. RESULTS: Euglycemic insulin infusion lowered arterial concentrations of free fatty acids, reducing myocardial extraction of free fatty acids by 85% and stimulated uptake of glucose and FDG. Myocardial glucose and FDG extraction fractions (%) increased from 1 +/- 1 and 2 +/- 2 at baseline to 8 +/- 2 and 10 +/- 3 during insulin infusion, respectively. The lumped constant value was estimated to be 1.44 +/- 0.14 (r = 0.87) for the fasted state, 0.99 +/- 0.07 (r = 0.74) during insulin infusion and 1.00 +/- 0.05 (r = 0.92) when both groups of data were pooled together. CONCLUSION: The data obtained in this study show that FDG uptake quantitatively traces glucose uptake during physiological hyperinsulinemia in patients with ischemic heart disease.

Effect of left ventricular function on the assessment of myocardial viability by technectium-99m sestamibi and correlation with positron emission tomography in patients with healed myocardial infarcts or stable angina pectoris, or both.

The accuracy of technetium-99m (Tc-99m) sestamibi single-photon emission computed tomography (SPECT) for the assessment of myocardial viability in patients with coronary artery disease and left ventricular (LV) dysfunction is not defined completely. This study determines whether the performance of Tc-99m sestamibi SPECT for viability detection differs between patients with mild-to-moderate coronary artery disease. Patients with regional and/or global LV dysfunction were separated into 2 groups on the basis of LV ejection fraction (EF) at rest: group 1 (LVEF > 25%, mean 36 +/- 6%, n = 9), and group 2 (LVEF < or = 25%, mean 17 +/- 5%, n = 11). All patients underwent semiquantitative Tc-99m sestamibi SPECT and positron emission tomography (PET) at rest with N-13 ammonia and F-18 fluorodeoxyglucose. The overall regional concordance of SPECT and PET for viability detection was 89% in group 1 and 78% in group 2 (p = 0.002). Discordance in group 2 was almost exclusively due to PET viable and/or SPECT nonviable regions. In regions with hypoperfusion at rest by PET, concordance was 78% in group 1 and only 64% in group 2 (p = 0.0015). In regions with reduced perfusion and relatively increased metabolic activity ("flow: metabolism mismatch"), Tc-99m sestamibi SPECT identified 88% of regions in group 1 as viable, but only 42% of regions in group 2 (p = 0.002). Thus, while Tc-99m sestamibi semiquantitative SPECT at rest shows a good concordance with PET for the detection of myocardial viability in patients with coronary artery disease with mild-to-moderate LV dysfunction, it may underestimate myocardial viability in patients with severe LV dysfunction, particularly in those patients with hypoperfusion at rest as assessed by PET.

Radiosynthesis and PET imaging of [N-methyl-11C]LY257327 as a tracer for 5-HT transporters.

No-carrier-added [N-methyl-11C]LY257327 was synthesized by methylation of the free base of the desmethyl precursor LY214281 with [11C]methyl iodide in anhydrous acetonitrile. Synthesis time was 52 +/- 3 min, radiochemical yield (based on [11C]methyl iodide) was 35 +/- 8%, radiochemical purity was 99 +/- 1%, and specific activity at EOB was 3900 +/- 1300 mCi/mumol. Two in vivo studies in baboon were carried out before and after pretreatment with the selective serotonin reuptake inhibitor citalopram. The first experiment showed high accumulation of radioactivity in midbrain, striatum, and thalamus, with slightly lower accumulation in the occipital and cerebellum regions. The radioactivity concentration peaked 5 min postinjection, decreasing steadily for the rest of the scanning time. The second experiment (blocked with citalopram) showed only partial inhibition of incorporation in all of the same brain regions. Although [N-methyl-11C]LY257327 displayed high brain uptake (5% of injected dose at 5 min postinjection) and localized in serotonergic areas of the brain, its target-to-nontarget ratio and its insensitivity to citalopram blocking suggest that its accumulation is dominated by nonspecific uptake. Therefore, [N-methyl-11C]LY257327 is not a useful agent for measuring serotonin reuptake sites in vivo by positron emission tomography.

Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse.

BACKGROUND: Short-term depletion of plasma tryptophan has been shown to result in depressive relapse in patients with remission of major depression. Positron emission tomography and single photon emission computed tomography studies implicated the dorsolateral prefrontal cortex, orbitofrontal cortex, thalamus, and caudate nucleus in the pathogenesis of depression. The purpose of this study was to measure cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. METHODS: Patients diagnosed as having major depression (N = 21) who clinically improved with serotonin reuptake inhibitors underwent 2 test days involving tryptophan depletion or placebo, followed 6 hours later by positron emission tomography scanning with fludeoxy-glucose F18. Brain metabolism was compared in patients with (n = 7) and without (n = 14) a tryptophan depletion-induced depressive relapse. RESULTS: Tryptophan depletion resulted in a decrease in brain metabolism in the middle frontal gyrus (dorsolateral prefrontal cortex), thalamus, and orbitofrontal cortex in patients with a depletion-induced depressive relapse (but not in patients without depletion-induced relapse). Decreased brain metabolism in these regions correlated with increased depressive symptoms. Baseline metabolism was increased in prefrontal and limbic regions in relapse-prone patients. CONCLUSION: Specific brain regions, including the middle frontal gyrus, thalamus, and orbitofrontal cortex, may mediate the symptoms of patients with major depression.

Diagnosis of pedal osteomyelitis with Tc-99m HMPAO labeled leukocytes.

The diagnosis of pedal osteomyelitis is often complicated by the presence of pre-existing bony abnormalities. In this study, the utility of radiolabeled white blood cell imaging for the detection of complicated pedal osteomyelitis was evaluated. Twenty-seven men and women were prospectively enrolled and underwent plain film radiography, three-phase bone scan, and Tc-99m hexamethylpropylamine oxine white blood cell scintigraphy of their feet. The presence or absence of osteomyelitis was confirmed in all subjects by microbiologic and histopatholigic analysis of resected bone tissue. The results indicated that white blood cell imaging was more sensitive (90%) and specific (86%) for infection than either bone scan (75% sensitive, 29% specific) or plain film radiography (55% sensitive, 57% specific). This preliminary study suggests that Tc-99m hexamethylpropylamine oxine-labeled white blood cell scintigraphy is a simple, accurate test for the detection of pedal osteomyelitis.