A new look at the cyclotron for making short-lived isotopes. 1966 -classical article-.

This reprint of an article that first appeared in Nucleonics in 1966 provides a unique perspective of the introduction of the cyclotron into clinical medicine and medical research. The cyclotron offers a potentially powerful tool to biomedical centers. With this accelerator one can produce a variety of short-lived nuclides that are unavailable from other sources.

A spheroid positron emission tomograph for brain imaging: a feasibility study.

UNLABELLED: It has been long recognized that the primary advantage of imaging the brain with a positron emission tomography using GSO scintillation detectors placed on a spheroid surface is the large solid angle of acceptance for annihilation radiation, which results in improved system sensitivity and image signal-to-noise ratio. In the present study, we investigated spheroid system geometry, detector design and contribution of scattered coincidences. METHODS: Scintillation detector distribution on a spheroidal surface was investigated by approximating the surface by polygons. Finding a suitable crystal for this purpose led to the development of an experimental GSO block-type detector. The fraction of scattered coincidences was experimentally evaluated using phantoms and detector pairs in conjunction with a testing platform, and the relationship between scattered fraction and phantom volume was obtained. RESULTS: Spheroid geometry was best implemented with a polyhedron consisting of a series of consecutive rings formed by trapezoids. An experimental block-type detector with 36 GSO scintillators and four 14-mm-diameter photomultiplier tubes, together with custom electronics, yielded a spatial resolution of 3.4 mm FWHM and an energy resolution of 18% FWHM. Using nearly "ideal" scintillation detectors with a 350-keV threshold, we found the scatter fraction to be 0.32 for a 20-cm uniform phantom, 0.22 for a 15-cm phantom and closely proportional to the square root of the phantom volume. CONCLUSION: For cerebral studies, a spheroid PET using GSO scintillators has several advantages: optimized geometry for sensitivity, a dead-time fivefold smaller than an equivalent BGO system, and appreciably better light output for improved energy resolution and detector identification. The construction of such a system is within the capabilities of present technology.

The super PET 3000-E: a PET scanner designed for high count rate cardiac applications.

OBJECTIVE: Mathematical models for the delineation of regional myocardial perfusion and metabolism with PET require faithful reconstruction of arterial and myocardial time-activity curves following administration of radiotracers. High temporal resolution is often required in such measurements. Many commercially available tomographs exhibit long dead times that limit their count rate capabilities. To overcome these limitations, we developed and tested a whole-body tomographic device (Super PET 3000-E) with high count rate capabilities. The use of cesium fluoride scintillation detectors coupled with a one-to-one detector photomultiplier configuration reduces the system resolving and dead times. MATERIALS AND METHODS: The Super PET 3000-E was subjected to a series of tests with phantoms to determine its resolution, sensitivity, linearity, count rate capabilities, dead time, and random coincidence contribution. RESULTS: The system sensitivity is 136 kcounts/s/microCi/ml and its transverse and longitudinal resolutions are 8.5 and 10.5 mm full width at half-maximum, respectively. The system can easily record a total event rate of 2.0 Mcounts/s with minimal dead time loss and excellent linearity. CONCLUSION: The system fulfills its design goals and allows the very high count rate performance needed for the application of the physiological models used in our cardiac studies.

The origins of positron emission tomography.

The development of positron emission tomography (PET) took place through the combination of the following recognitions: (1) a handful of short-lived, positron-emitting radionuclides, carbon-11, nitrogen-13, and oxygen-15, exhibit chemical properties that render them particularly suitable for the tracing of important physiological pathways, and (2) the radiation emitted as a result of the annihilation of positrons in matter exhibited physical properties that made it well-suited for nuclear medicine imaging, particularly for tomographic reconstruction. The scientific building blocks that were necessary for the structure of PET were contributed over a period of several decades by many investigators in physics, mathematics, chemistry, and fundamental biology.

Positron emission tomography in the study of acute radiation effects on renal blood flow in dogs.

Renal blood flow measurements have been carried out by means of positron emission tomography (PET) to facilitate the detection of radiation-induced injuries. The advantages of the method employed in animal experiments are described.

Delineation of impaired regional myocardial perfusion by positron emission tomography with H2(15)O.

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.

PET measurement of regional lung density: 1.

Regional lung density (LD) and lung water (LW) measurements were made with positron transmission and emission tomography (PET) in normal and edematous lung in supine dogs in vivo. A comparison was also made of LD measurements by PET and X-ray CT (used by others to noninvasively assess pulmonary edema). Mean LW was 0.25 +/- 0.06 ml water/ml lung and the mean LD (PET) was 0.32 +/- 0.06 g/ml lung (average ratio of LW to LD was 0.795 +/- 0.041). The LD measurements ranged from 0.25 +/- 0.06 in anterior portions of lung to 0.43 +/- 0.11 g/ml in posterior areas, but the ratio of LW to LD was similar throughout the lung. The LW and LD measurements obtained in both normal and edematous portions of lung were strongly correlated (r = 0.886). Values for LD by PET were consistently higher than values obtained for LD by X-ray CT. These differences are probably due to beam-hardening effects with CT and partial-volume averaging and scattered radiation effects with PET. Nevertheless, PET-LD measurements may be a satisfactory method for following acute changes in LW or for normalizing other PET-derived data.

Quantitative measurement of regional pulmonary blood flow with positron emission tomography.

We have measured regional pulmonary blood flow (PBF) in normal dogs with positron emission tomography (PET) and 15O-labeled water (H2(15)O). The method is nondestructive, quantitative, and repeatable. To measure PBF, PET is used to measure both the initial and equilibrium distribution of lung activity after H2(15)O infusion. The data are then interpreted with a one-compartment mathematical model. Measurements of PBF in dogs with H2(15)O (PBF-water) were compared with PBF measured with 68Ga microspheres (PBF-MS), and a close correlation was observed: PBF-water = 0.82 PBF-MS + 25.4 (R = 0.97, n = 52). In another set of animals an important assumption of the method, namely that the tracer is fully extracted during a single pass through the lung, was demonstrated using a single-probe residue-detection technique. Computer simulations were performed to illustrate the sensitivity of the method to errors in the measured variables of tracer activity or tissue-blood partition coefficient. Results showed only small error magnification for the range of values observed in these studies.

Radioactive oxygen-15 in the study of cerebral blood flow, blood volume, and oxygen metabolism.

The short half-life of 15O led early observers to believe that it was unsuitable for use as a biological tracer. However, initial studies with this nuclide demonstrated its potential usefulness for in vivo, regional physiologic measurements. Subsequently, techniques were developed to measure cerebral blood flow (CBF), blood volume, and oxygen metabolism using intracarotid injection of 15O-labeled radiopharmaceuticals and highly collimated scintillation probes to record the time course of radioactivity in the brain. The development of positron emission tomography (PET) made possible the in vivo, noninvasive measurement of the absolute concentration of positron-emitting nuclides. A variety of tracer kinetic models were formulated to obtain physiologic measurements from tomographic images of the distribution of 15O-labeled radiopharmaceuticals in the brain. 15O-labeled carbon monoxide, administered by inhalation, binds to hemoglobin in RBCs, and therefore can be used as a intravascular tracer to measure regional cerebral blood volume (rCBV). Several strategies have been developed to measure regional CBF using 15O-labeled water as an inert, diffusible flow tracer. Regional cerebral oxygen metabolism is measured using scan data obtained following the inhalation of 15O-labeled oxygen; independent determinations of local blood flow and blood volume are also required for this measurement. The tracer kinetic models used to measure rCBV, blood flow, and oxygen metabolism will be described and their relative advantages and limitations discussed. Several examples of the use of 15O tracer methods will be reviewed to demonstrate their widespread applicability to the study of cerebral physiology and pathophysiology.

Regional lung water and hematocrit determined by positron emission tomography.

We have measured with positron emission tomography (PET) the regional distribution of extravascular lung water (EVLW) and hematocrit (HctL) in normal supine dogs. H2(15)O and C15O were used as total lung water (TLW) and intravascular water (IVW) compartment labels, respectively. An additional plasma volume label (68Ga-transferrin) was used to determine regional HctL. EVLW was calculated as the difference between TLW and IVW. In 13 dogs, EVLW was relatively constant along a gravity-dependent vertical gradient, although values in the most anterior regions were statistically less (P less than 0.05) than those in more posterior ones. The average value for EVLW (13 dogs) was 14.4 +/- 2.5 ml H2O/100 ml lung. When EVLW was compared with IVW on a regional basis, the EVLW/IVW ratio decreased significantly in a gravity-dependent direction from 1.95 +/- 0.28 to 0.88 +/- 0.18. In 7 dogs, no significant difference between HctL and systemic hematocrit (average ratio 1.01 +/- 0.08) was found nor was any significant variation of HctL within the lung detected. Thus, in contrast to gravimetric techniques, a hematocrit correction does not appear to be necessary when regional EVLW is studied by PET.

Improvement of regional myocardial metabolism after coronary thrombolysis induced with tissue-type plasminogen activator or streptokinase.

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.

Cost analyses of positron emission tomography for clinical use.

Costs associated with the clinical use of positron emission tomography (PET) at the Mallinckrodt Institute of Radiology are analyzed according to the two major components: radiopharmaceutical production and imaging. Estimated annual costs are +584,500 for PET radiopharmaceutical production and +644,250 for PET imaging (1982 U.S. dollars). The economic break-even point charge to cover expenses is +615-+2,780 per clinical procedure, depending on several variables, especially procedure volume. Charges for PET clinical procedures will be among the highest of all charges for diagnostic imaging procedures, perhaps even higher than these estimates at some institutions. Several technologic and procedural approaches to reducing costs are suggested, the most promising being the anticipated availability of positron-emitting radionuclides from commercial suppliers.

Clot-selective coronary thrombolysis with tissue-type plasminogen activator.

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.

Altered regional myocardial metabolism in congestive cardiomyopathy detected by positron tomography.

The present study was performed to determine whether positron emission tomography performed after intravenous injection of 11C-palmitate permits detection and characterization of congestive cardiomyopathy. Positron emission tomography was performed after the intravenous injection of 11C-palmitate in 13 normal subjects, 17 patients with congestive cardiomyopathy, and six patients with initial transmural myocardial infarction (defined electrocardiographically). Regionally depressed accumulation of 11C-palmitate was assessed, characterized, and quantified in seven parallel transaxial reconstructions in each patient. Normal subjects exhibited homogeneous accumulation of 11C-palmitate within the left ventricular myocardium, with smooth transitions in regional content of radioactivity. Patients with cardiomyopathy exhibited marked spatial heterogeneity of the accumulation of palmitate throughout the myocardium, easily distinguishable from that in normal subjects and distinct from that observed in patients with transmural infarction, in whom discrete regions of depressed accumulation of palmitate were observed with residual viable myocardium accumulating palmitate homogeneously. Patients with cardiomyopathy exhibited a larger number of discrete noncontiguous regions of accumulation of palmitate within the myocardium than either control subjects or patients with transmural infarction (17.4 +/- 0.6 [SEM] versus 11.8 +/- 0.7 versus 10.3 +/- 0.6, p less than 0.005). Similarly, regions of accumulation of palmitate were irregularly shaped in patients with cardiomyopathy, with a longer normalized perimeter than either control subjects or patients with transmural infarction (2.0 +/- 0.05 versus 1.8 +/- 0.06 versus 1.9 +/- 0.09, p less than 0.05). Regional abnormalities of the accumulation of 11C-palmitate could not be explained by regional differences in left ventricular wall motion or myocardial perfusion. Thus, marked heterogeneity of regional myocardial accumulation of 11C-palmitate is detectable and quantifiable in patients with congestive cardiomyopathy by positron emission tomography and may be particularly valuable for early detection and characterization of cardiomyopathy.