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The physical characteristics and some imaging capabilities of Super PETT I, a positron emission tomograph utilizing time-of-flight (TOF) in its image reconstruction process were assessed experimentally by means of measurements carried out in phantoms and clinical imaging studies. The performance characteristics assessed included sensitivity, spatial resolution, image improvements resulting from time-of-flight information utilization, system dead time, and linearity. The clinical examples included imaging of the brain, the heart, the liver, and a demonstration of Super PETT I's capability of achieving cardiac gating.

The extraction of 15 O-labeled water by the brain during a single capillary transit was studied in vivo in 20 adult rhesus monkeys by external detection of the time course of the tracer subsequent to the internal carotid injection of 0.2 ml of whole blood labeled with H 2 15 O. The data showed that labeled water does not freely equilibrate with the exchangeable water in the brain when the mean cerebral blood flow exceeds 30 ml/100 g min -1 . At the normal cerebral blood flow in the rhesus monkey (∼50 ml/100 g min -1 ), only 90% of the H 2 15 O is extracted during a single capillary transit. In addition, cerebral blood flow was determined with H 2 15 O and 133 Xe in these monkeys using residue detection and employing the central volume principle. The data supported the hypothesis that a diffusible tracer, H 2 15 O, need not be in complete equilibrium between the phases of a system for the application of the central volume principle to be valid. Finally, the brain capillary permeability-surface area product was computed from these data; it was approximately 0.023 cm 3 /sec g -1 .

To characterize externally detectable changes in myocardial metabolism of free fatty acids (FFA) and glucose associated with ischemia, isovolumically beating rabbit hearts were perfused under conditions of selected flows with cyclotron-produced, short-lived (t1/2 - 20.4 minutes), 11C-labeled isotopes of glucose and FFA. Tension-time index decreased 83% and lactate production increased from 0.5 +/- 1.9 (SE) to 5.3 +/- 2.1 mumol/min per g of dry weight reflecting myocardial ischemia after flow was reduced from 20 to 5 ml/min. After 30 minutes of low flow the myocardial accumulation of 11C-octanoate, expressed as the extraction fraction, declined from 56 +/- 15% to 30 +/- 3%, reflecting metabolic suppression of FFA extraction during low flow. Effects attributable exclusively to prolonged residence time were excluded. Similar results were obtained with 11C-palmitate. The myocardial avidity for 11C-palmitate was demonstrable by rectilinear whole body scanning in dogs given 5 mCi of the agent intravenously. Diminished 11C-palmitate uptake in zones of myocardium rendered ischemic for 20 minutes prior to reflow in intact dogs was delineated by electrocardiographically gated positron-emission transaxial computer reconstruction tomography. Thus, diminished 11C-FFA extraction, externally detectable, accompanies decreased perfusion in isolated perfused hearts, and decreased 11C-FFA uptake reflecting myocardial ischemia in vivo can be evaluated noninvasively by positron-emission transaxial tomography.

Regional cerebral oxygen utilization rate is measured in vivo by the following method: A small volume of blood with radioactive oxygen-15-tagged hemoglobin is rapidly injected into the internal carotid artery of the patient under study. The first injection is followed by the injection carried out under identical circumstances but with blood labeled with water-15O. After each injection, the distribution of the radioactive label in the brain is measured and recorded, as a function of time, by six collimated scintillation probes placed over the subject's head. The recording, subsequent to the first injection, reflects (a) the arrival of the labeled oxygen into the tissues, (b) its partial conversion into water of metabolism, and (c) the washout of labeled water from the brain. The ratio of the amount of labeled water formed to the amount of oxygen perfusing the tissues, which can be derived from the recording, is a measure of fractional oxygen utilization. The second injection provides a measure of blood flow by the interpretation of the washout of labeled water from brain tissues. The product, fractional oxygen utilization × blood flow × arterial oxygen content, gives a measure of oxygen utilization rate. Some aspects of the validity of this method are tested by the injection of a nondiffusible indicator, carboxyhemoglobin-15O. Regional cerebral oxygen utilization rates for a series of patients with cerebral pathology are reported.

Coronary thrombolysis, an intervention that can abort the sequelae of acute myocardial infarction, was accomplished within 10 minutes in dogs by intravenous administration of clot-selective, tissue-type plasminogen activator. In addition to inducing clot lysis, this promising fibrinolytic agent restored intermediary metabolism and nutritional myocardial blood flow, detectable noninvasively with positron tomography, without inducing a systemic fibrinolytic state.

To determine whether positron emission tomography (PET) after the combined administration of /sup 11/C-palmitate intravenously to image myocardium and /sup 11/CO by inhalation to image the cardiac blood pool with /sup 11/CO-hemoglobin provides quantitative delineation of the locus and extent of myocardial infarction, 28 patients with suspected myocardial infarction were studied. Twenty-one patients had electrocardiographically documented transmural infarction and in seven, the diagnosis of infarction was ultimately excluded based on enzymatic and electrocardiographic criteria. To assess reproducibility, four patients were studied on two occasions 1 month apart. Inferior and apical infarcts were readily localized with sagittal and coronal as opposed to transaxial reconstructions. Complete electrocardiographic and tomographic concordance was observed for the locus of all transmural infarcts. Reproducibility of tomographic estimates was within 10%. Tomographic estimation of the extent of infarction with /sup 11/C-palmitate in a subset of patients in whom right ventricular contributions to overall enzyme release could be excluded was facilitated by delineation of the endocardial border with the /sup 11/CO-hemoglobin cardiac blood pool image in the same plane. The correlaion between enzymatic (serial plasma MB-CK method) and tomographic estimates of infarct size was close (r = 0.92). Thus, as has been shown in experimental animals, PET withmore » /sup 11/C-palmitate permits quantification and localization of myocardial infarcts in patients.« less

The relationships between cerebral blood volume (CBV), cerebral blood flow (CBF), and the cerebral vascular mean transit time (t v ) during acute changes in the Pa CO 2 over a range of 15 to 76 torr were investigated in vivo in rhesus monkeys by serially determining the mean transit time of a vascular tracer, 15 O-labeled carboxyhemoglobin, and the mean transit time of a diffusible tracer, 15 O-labeled water. Over this range of Pa CO 2 , a significant linear relationship of CBV = 0.041 Pa CO 2 + 2.0 was found. For each one torr change in Pa CO 2 , there is a change in CBV of 0.041 ml/100 gm of perfused tissue. At a normocarbic value of Pa CO 2 (37 torr), an average value of 3.5 ml/100 gm was found. A nonlinear relationship of CBV and CBF was found. This relationship is expressed in the equation, CBV = 0.80 CBF 0.38 . A significant linear relationship was found between CBF and Pa CO 2 . This was described by the equation, CBF = 1.8 Pa CO 2 - 16.75. For each one torr change in the PaCO 2 , there is a 1.8 ml/100 gm per minute change in the CBF. At a normocarbic value of Pa CO 2 (37 torr), an average value of CBF of 50 ml/100 gm per minute was found. The relationship of CBV and t v was nonlinear and was expressed in the equation, t C15O = 41 CBF -0.62 .

A method for the in vivo determination of cerebral blood volume was tested in 15 adult rhesus monkeys. The technique utilized external residue detection and required the serial measurement of two mean transit times, namely, that of an intravascular tracer, C15O-hemoglobin, and that of a diffusible tracer, H215O. In computing the mean transit time for the intravascular tracer, the conventional Hamilton extrapolation of the downslope of the recording obtained for the washout of the tracer from the brain subsequent to an intracarotid bolus injection was found to be inadequate, yielding a mean transit time that systematically underestimated that parameter. Alternatively, the use of a power law extrapolation, as proposed by Huang, allowed a more accurate prediction of the vascular mean transit time. The preliminary studies testing the method predicted that the relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF) was adequately represented by the equation CBV = 0.80CBF0.38, with a correlation coefficient of r = 0.90 for the cerebral blood flow range of 16 to 134 ml/100 g min-1 with a normocapnic cerebral blood volume of 3.5 ml/100 g perfused brain tissue (arterial Pco2 = 37 torr, CBF = 50 ml/100 g min-1).

To assess the effects on the heart itself of coronary thrombolysis induced with either tissue-type plasminogen activator (t-PA) or streptokinase (SK), we performed positron emission tomography with 11C-palmitate in 19 patients with initial transmural myocardial infarction immediately after admission and again within 48 to 72 hr after intracoronary administration of t-PA (n = 2) or SK (n = 17). Clots were persistent in eight patients treated with SK despite an average dose of 336,000 IU, sufficient to markedly deplete fibrinogen. In the absence of lysis, favorable tomographic changes did not occur. In contrast, in each of the 11 patients in whom lysis was induced (two with t-PA and nine with SK) myocardial accumulation of 11C-palmitate improved by an average of 29% in late compared with early studies (p less than .001). Results were comparable in patients with anterior and those with inferior infarction. Thus clot lysis induced with either t-PA or SK led to improved regional myocardial metabolism.

A study was performed to determine whether viable, but ischemic, tissue could be detected and localized in vivo based on external detection of impaired fatty acid metabolism. Accordingly, regional clearance of /sup 11/C-palmitate was assessed by sequential PET in 15 anesthetized dogs. Clearance was consistently monoexponential from 5-15 minutes after administration of the tracer. In the absence of coronary stenosis (n = 7), clearance was homogeneous throughout the heart, with an average rate constant (k) of -0.060 +/- 0.005 min/sup -1/ (+/- SEM) and a coefficient of variation (CV) of 11.1 +/- 2.1% in each heart. Homogeneity persisted when the heart rate was increased from 84.4 +/- 6.0 to 202.7 +/- 11.5 beats/min with atropine (CV 13.2 +/- 3.5%). With left circumflex coronary stenosis (less than or equal to70% reduction in vessel diameter), homogeneity of /sup 11/C-clearance under control conditions and with tachycardia did not differ from clearance in hearts without coronary stenosis. However, with stenosis >70% sufficient to induce ischemia without gross infarction, regional clearance of /sup 11/C became markedly heterogeneous under control conditions (CV 28.1 +/- 5.5%, p

Ischemic myocardial injury has been detected recently in isolated perfused hearts and intact experimental animals with positron-emitting 11C-palmitate and reconstructive tomography providing cross-sectional images of the heart free from superimposed activity in overlying structures. To evaluate the applicability of positron emission transaxial tomography in detecting infarction in man, 10 normal human subjects and 12 patients who sustained documented acute myocardial infarction three to 12 months previously were studied. Tomograms were obtained after intravenous injection of 5 to 10 mCi of 11C-labeled palmitate, a physiological substrate of myocardium. Tomograms from all normal subjects exhibited homogeneous distribution of 11C-palmitate throughout each 1.5 cm thick cross section of the ventricle. Tomograms from all patients with remote anterior or inferior and posterior myocardial infarction exhibited diminished accumulation of 11C-palmitate delineating regions corresponding to the electrocardiographic locus of infarction. The distribution of 11C-palmitate detectable by positron emission transaxial tomography in a series of cross sections from apex to base in the same normal subject or patient with remote myocardial infarction was analogous to that observed in normal dogs and animals with experimentally induced myocardial infarction.

Positron emission tomography with 15O-labeled water (H2(15)O) can be used to delineate abnormal regional myocardial blood flow in experimental animals. To determine the feasibility of this method in humans, we studied 33 subjects (9 normal volunteers and 24 patients with angiographically documented coronary artery disease) at rest and after myocardial hyperemia induced with intravenous infusion of dipyridamole. At rest, the myocardial region demonstrating the lowest relative H2(15)O activity exhibited 71 +/- 8% of activity in the region with peak activity in control subjects and 62 +/- 17% in patients (p = NS). After the dipyridamole infusion, differences between the two groups were accentuated. In control subjects, activity in the region with lowest relative radioactivity averaged 77 +/- 5% of that in the region with peak activity. In patients, it averaged 55 +/- 22% of activity in the region with peak activity (p less than 0.01). Results in patients with ischemia with or without a history of remote myocardial infarction were not significantly different. In 22 of the 24 patients, the region with lowest relative perfusion corresponded anatomically to the region of myocardium distal to a stenosis. Thus, delineation of regional myocardial perfusion in patients with coronary artery disease is possible with positron emission tomography and H2(15)O. Further studies will be necessary to prospectively determine sensitivity and specificity.

To assess myocardial infarction quantitatively in 15 mm thick transverse sections of the canine heart in vivo we utilized a new technique, positron emission transaxial tomography (PETT) and cyclotron-produced 11C-palmitate (11C-P) injected intravenously. Results were compared to regional myocardial creatine phosphokinase (CPK) depletion, diminished 14C-palmitate accumulation in tissue extracts, and infarction estimated morphometrically 48 hours after coronary occlusion. CPK activity and 14C-P content declined in parallel in transmural biopsies (N=44) from normal and ischemic zones (r=.92) in six dogs; and infarct in 10 mm thick cross sections of the entire left ventricle estimated morphometrically (N=26) in six other animals correlated with CPK depletion in contiguous 2.5 mm thick slices (r=.92). When the percentage of infarction in 15 mm thick cross sections was assessed tomographically in six other dogs 48 hours after coronary occlusion with 11C-P injected intravenously, results correlated with infarction in corresponding cross sections from the same hearts estimated morphometrically (r=.97, N=9) and by analysis of CPK depletion (r=.93, N=9). Thus, PETT permits estimation of infarction in cross sections of the left ventricle in vivo after intravenous injection of 11C-palmitate.

In an attempt to evaluate the possible usefulness of transmission computed tomography, CT scans of the chest of a series of dead dogs were obtained by means of an EMI body scanner. The sections thus obtained with and without the injection of contrast material reveal a great deal of cardiac morphology. Infarcts of the heart produced prior to scanning were imaged as regions of lower x-ray attenuation. The hearts of a series of live dogs following infarction were imaged by means of a positron emission transverse tomomograph (PETT) following administration of C-palmitate. The images permitted assessment of the relative size of the infarct. The relative advantages of transmission and emission tomography in cardiac visualization are discussed.

The present study was performed to determine whether positron emission tomography (PET) performed after i.v. 11C-palmitate permits detection and characterization of nontransmural myocardial infarction. PET was performed after the i.v. injection of 11C-palmitate in 10 normal subjects, 24 patients with initial nontransmural myocardial infarction (defined electrocardiographically), and 22 patients with transmural infarction. Depressed accumulation of 11C-palmitate was detected with sagittal, coronal and transverse reconstructions, and quantified based on 14 contiguous transaxial reconstructions. Defects with homogeneously intense depression of accumulation of tracer were detected in all 22 patients with transmural infarction (100%). Abnormalities of the distribution of 11C-palmitate in the myocardium were detected in 23 patients with nontransmural infarction (96%). Thallium scintigrams were abnormal in only 11 of 18 patients with nontransmural infarction (61%). Tomographically estimated infarct size was greater among patients with transmural infarction (50.4 +/- 7.8 PET-g-Eq/m2 [+/- SEM SEM]) compared with those with nontransmural infarction (19 +/- 4 PET-g-Eq, p less than 0.01). Residual accumulation of 11C-palmitate within regions of infarction was more intensely depressed among patients with transmural compared to nontransmural infarction (33 +/- 1 vs 39 +/- 1% maximal myocardial radioactivity, p less than 0.01). Thus, PET and metabolic imaging with 11C-palmitate is a sensitive means of detecting, quantifying and characterizing nontransmural and transmural myocardial infarction.

The gain achieved in image quality by utilizing, in the image forming process, the time-of-flight information (TOF) of positron annihilation photons between their inception and detection was measured experimentally by means of a positron emission tomograph (PET)-Super PETT I. The measurements were carried out by imaging a 35 cm cylindrical uniform phantom containing different positron activity concentrations. The gain achieved through the incorporation of TOF information, defined as the ratio of variances in images reconstructed with and without TOF information, was found to be approximately 3 at the lowest activity concentration and 5-8 in the activity concentration range typically encountered in clinical studies especially in fast or dynamic studies. This increase in gain with activity was interpreted as resulting from the reduction of random coincidences when TOF information is used. Further image improvement is yielded by incorporating TOF information into the PET attenuation correction provided by the measurement of transmission of annihilation photons in the object imaged.

Cerebral blood flow (CBF) remains constant over a wide range of arterial blood pressure. This is thought to be accomplished by changes in the diameter, and therefore the volume, of the cerebral resistance vessels. To test this hypothesis, regional cerebral blood volume (rCBV) was measured in vivo in Rhesus monkeys over a range of mean arterial blood pressures (MABP) of 35 to 200 torr. Multiple measurements were made in each animal by the method of stimulated x-ray fluorescence. A significant linear relationship of rCBV = 6.26 (±0.47 SD) -0.015 (±0.004 SD) MABP was found. For each one torr change in the MABP, there is a change in rCBV of 0.015 cc/100 gm of brain tissue over a range of MABP of 35 to 200 torr. An additional observation of this investigation was that autoregulation of the cerebral blood flow (CBF) is perturbed for a period lasting up to 15 minutes after the intravenous injection of Renografin 76 R .

A miniature scintillation detector recently designed and constructed in this laboratory can be inserted into the esophagus and under fluoroscopic vision positioned so that radioactivity emitted from the blood in the descending aorta can be detected and a time-concentration curve recorded from which cardiac output can be determined. Twenty simultaneous determinations of cardiac output by the isotope-dilution method with the esophageal scintillation counter probe and the dye-dilution technique were done in 10 dogs. There was a good correlation between the two methods. Among the technical advantages of the isotope-dilution method over the dye-dilution method are avoidance of arterial puncture, only one sample of venous blood required, an easily performed procedure, and ability to permit repeated determinations of cardiac output with a minimum of manipulation and trauma.

The possibility of utilizing the PET approach to the investigation of dynamic physiologic processes has not been limited so far by radiation exposure to the patient but rather considerations by the technical limitations of PET imaging devices. In the past few years, several PET designs have been optimized specifically for fast dynamic studies. The most recent of these designs incorporates cesium fluoride detectors to achieve high counting rate capabilities. At this time, the value of fast dynamic studies with PET can be only theorized but expectations for this modality rest on solid physiologic hypotheses. The incorporation of time-of-flight information into the PET reconstruction process promises to further enhance the capabilities of fast PET devices by the improvement of temporal resolution through signalto-noise ratio increase. PET devices incorporating time-of-flight information are beyond the drawing board stage and are now under construction.

Emission tomography can be used to monitor, in vivo and regionally, the utilization of metabolic substrates labeled with positron-emitting radioisotopes produced by a cyclotron. The concept was validated by measuring brain glucose utilization with carbon--11-labeled glucose in rhesus monkeys.

The acute 30-day median lethal dose in Hartley guinea pigs was determined for cobalt-60 gamma -irradiation. The median lethal dose was found to be 326 rads, Change in weight of the irradiated animals was recorded for a period of 30 days. Extravasation of blood into viscera and serous cavities was the most frequent finding at autopsy. (auth)

The production of short-lived radioactive gases for medical studies is discussed with regard to the chemical reactions in suggested targets. The chemistry of target materials was studied by using the technique of radio-gas-liquid partition chromatography to analyze the product gases. Based on the chemistry of the reactions of oxygen-15 in oxygen-nitrogen mixtures, and carbon-11 in boric oxide, targets were designed for the production of oxygen-15-labeled oxygen, oxygen- 15-labeled carbon monoxide, and carbon-11-labeled carbon monoxide in high yields and high radio-chemical purity.