Perfusion Agent Research Articles

Brain single-photon emission computed tomography for behavior disorders in children

Single-photon emission computed tomography (SPECT) of the brain has been used to define functional abnormalities in two groups of childhood behavior disorders: (1) a "primary" category in which there is exclusive or predominant presentation with cognitive and/or behavioral dysfunction and (2) encephalopathies, often defined etiologically at the biochemical or molecular level, in which clinical expression includes, but is not confined to, neural dysfunction. Radiopharmaceuticals available for such studies are manifold, but those used to date have been predominantly perfusion agents, eg, Xenon-133 (133Xe) and technetium-99m (99mTc) hexamethylpropylene amine oxime, and studies with [99mTc]bicisate are eagerly awaited. Xenon-133 studies require that the patient be in the field of view of the detector while the tracer is administered. This renders it difficult for a subject to perform cognitive and other exercises while being imaged, because the environment is quite foreign. On the other hand, the 99mTc-labeled perfusion agents permit a scintigraphic "snapshot" of regional cerebral blood flow during a behavioral event without having to have the patient under the imaging instrument. Thus, one can separate the administration of the radiotracer, which can be done under more controlled and physiological conditions, from the actual imaging. In addition, greater spatial resolution is achieved with the technetium-based agents. Currently, multidetector or dedicated annular crystal-type cameras are the preferred brain SPECT devices, and they are essential to applications such as cortical "activation mapping" or tomographic detection of receptor systems. Close attention to technical detail and standardization of the child's behavioral environment during the investigation are critical to a successful study. The relative advantages and disadvantages of qualitative versus semiquantitative analysis of imaging date are reviewed. Among primary behavioral disorders, 133Xe SPECT studies in attention deficit disorder-hyperactivity (ADHD) have suggested a pattern of hypoperfusion of striatal and periventricular structures with sensorimotor cortical hyperperfusion. This pattern is consistent with some neurophysiological models of the disorder. In cerebral palsy, perfusional abnormalities have paralleled clinical deficits and may offer information to help predict outcome. The important field of childhood affective disorders (schizophrenia, juvenile autism, depression, etc) remains largely unstudied with SPECT. Finally, representative examples of the use of SPECT to study perfusion in encephalopathies with behavioral expression (phenylketonuria, MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome, Wilson's disease, etc) are given.

Adenosine myocardial perfusion imaging in the noninvasive diagnosis and prognosis of coronary artery disease

AbstractAdenosine is a purine base compound which is of fundamental importance in many physiologic processes in the body, including vasodilation in most arterial vascular beds. Adenosine produces maximal or near‐maximal coronary vasodilation by interacting with the adenosine A2 receptors in the cell wall, on a dose dependent fashion. The mechanism of thallium‐201 myocardial perfusion defects induced by adenosine scintigraphy is a heterogeneity of myocardial blood flow due to a greater coronary flow increase in the normal arteries and a lesser increase in the stenotic arteries. The ultra‐short half‐life of adenosine (< 10 sec) necessitates continuous intravenous administration at a dose of 140 μg/kg/min for six min. The excellent safety record of this regimen has been demonstrated in several thousand patients in the United States. Side effects occur in most patients during adenosine infusion. Chest pain occurs often and in some cases may be due to a true coronary steal phenomenon. In the author's experience, first degree AV block occurs in approximately 10% and second or third degree AV block in approximately 4% of the patients, and are due to the negative dromotropic effect of adenosine on the AV node. On the positive side, these untoward effects are very short‐lived and typically disappear within one or two minutes after discontinuing the adenosine infusion. No serious complications or fatalities have been observed to date with this test. The cumulative experience with adenosine thallium‐201 scintigraphy indicates high sensitivity and specificity in the diagnosis of coronary artery disease. Recent data also suggest it may be an excellent technique to assess a patient's prognosis early after a myocardial infarction. Adenosine‐induced coronary vasodilation, in combination with thallium‐201 or the new technetium‐99m perfusion agents, holds great promise in the assessment of patients with coronary artery disease. © 1993 Wiley‐Liss, Inc.

New directions in myocardial perfusion imaging

In recent years, substantial progress has been made in the field of nuclear cardiology. Pharmacologic stress perfusion imaging with intravenous administration of dipyridamole or adenosine provides comparable sensitivity and specificity values for detection of coronary artery disease (CAD) as exercise imaging and has been employed successfully for risk stratification prior to peripheral vascular or aortic surgery and after myocardial infarction. Detection of myocardial viability can be enhanced utilizing reinjection of a second dose of thallium-201 (Tl-201) at rest after acquisition of redistribution images with the single photon emission computerized tomography (SPECT) technique. Imaging solely in the resting state with Tl-201 can also provide information concerning presence of viable myocardium in asynergic regions that are stunned or hibernating. New technetium-99m (Tc-99m) perfusion agents have emerged in the clinical setting and have provided excellent predictive value for detection of CAD in patients with chest pain and permit simultaneous assessment of function and regional blood flow. Tc-99m Sestamibi, one of these agents, is also a valid marker of viability when assessing myocardial salvage after coronary reperfusion in acute myocardial infarction.

Synthesis and in vivo behavior of a copper‐64‐labeled dithiosemicarbazone derivative coupled to a dihydropyridine carrier

AbstractThe dihyropyridine ⇄ pyridinium salt redox delivery system was used to develop a perfusion agent that could be labeled with a generator‐produced positron emitter 62Cu. A 64Cu‐labeled dithiosemicarbazone (DTS) molecule attached to a dihyropyridine carrier (PDTS‐DHC) was synthesized by the simple mixing of 64Cu acetate and Zn‐PDTS‐DHC. The latter was prepared by dithionite reduction of the Zn complex of a corresponding pyridinum precursor (PDTS‐QC+). When injected into mice, 64Cu‐PDTS‐DHC showed a high myocardial uptake and high heart‐to‐blood and heart‐to‐lung ratios. These results demonstrate that it may be possible to develop 62Cu‐PDTS‐DHC compounds as radiopharmaceuticals for myocardial perfusion studies using positron emission tomography.

The relationship between myocardial retention of technetium-99m teboroxime and myocardial blood flow

Objectives. The aim of this study was to define the temporal changes in the relationship between technetium-99m teboroxime tissue retention and myocardial blood flow in a canine model.Background. Technetium-99m teboroxime is a new neutral lipophilic myocardial perfusion agent. It is known to be highly extracted by the myocardium but to have a rapid clearance rate.Methods. A wide range of myocardial blood flow was induced in each experiment by regional coronary occlusion and dipyridamole infusion. Myocardial retention of technetium-99m teboroxime was determined by in vitro tissue counting at 1, 2 or 5 min after injection of the tracer. Tracer retention was correlated with microsphere-determined blood flow and the data were fitted to nonlinear functions.Results. Correlation coefficients for these functions were 0.92, 0.95 and 0.95 at 1, 2, and 5 min, respectively. At 1 min after injection, the relationship of technetium-99m teboroxime retention to blood flow was linear over a wide flow range, becoming nonlinear at flow rates > 4.5 ml/min per g. After 5 min the retention-flow relationship was linear only to 2.5 ml/min per g, above which little change in retention was noted. Normalized myocardial retention, expressed as a percent of the retention at 1 ml/min per g, was also calculated. At flow rates of 1, 2, 3, 4 and 5 ml/min per g, normalized retention was 100, 169, 228, 277 and 317% at 1 min and 100, 171, 217, 239 and 237% at 5 min after injection.Conclusions. At 1 min after injection, the relationship of technetium-99m teboroxime myocardial retention to blood flow is well maintained over a wide range of flow. However, after only 5 min, tracer retention underestimates flow changes at moderate and high flow rates. Thus, rapid acquisition protocols are necessary to fully exploit the potential of this promising new tracer in the evaluation of myocardial perfusion.

Isolated cardiomyocytes in conjunction with NMR spectroscopy techniques to study metabolism and ion flux.

To distinguish cellular from vascular responses to physiological and pathophysiological stimuli, we developed methods to perform NMR spectroscopy on isolated ventricular cardiomyocytes. Isolated adult rat cardiomyocytes, placed in agarose beads and superfused with phosphate-free buffer (Media 199 (GIBCO 400-1100) gassed with 95% O2, 5% CO2), were used to evaluate a variety of cellular processes during different pharmacological and physiological interventions. Bioenergetic function was monitored with 31P NMR. Intermediary metabolism, gluconeogenesis, and glycolysis were monitored with 13C NMR. Sodium flux was monitored with 23Na NMR. Calcium flux was monitored with 19F NMR in conjunction with an intracellular calcium-chelating agent, 5F-1,2-bis(2-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid. Creatine kinase kinetics (forward rate constant (Kf) and flux of phosphocreatine to ATP) were estimated with 31P NMR saturation transfer data. Various combinations of NMR parameters were monitored simultaneously so that the interaction of metabolism and ion flux could be evaluated. We have demonstrated that it is possible to simultaneously monitor a variety of cellular processes in intact heart cells in real time, without the confounding influences of perfusion, contractile function, and extrinsic blood-borne neurohumoral agents. This model will be useful for longitudinal studies of myocyte metabolism and ion flux.

Prediction of muscle viability after electrical burn necrosis.

In this preliminary study, Tc-99m MIBI, a muscle perfusion agent, was used to assess the viability of tissues in two patients with extensive high-tension electrical burns. This proved to be an easy and definitive diagnostic procedure and a practical solution to determining the level of amputation before surgery.

Evaluation of changes in myocardial function on exercise in patients with coronary artery disease using gated MIBI scintigraphy.

Technetium-99m-methoxy-isobutyl-isonitrile (MIBI) is a myocardial perfusion agent which allows simultaneous assessment of left ventricular function. We evaluated left ventricular (LV) function with exercise using a new method of myocardial profiling in 43 patients with chest pain. Twenty-eight had significant coronary artery disease and 15 were normal on coronary angiography. Results were compared to equilibrium radionuclide ventriculography. MIBI fractional shortening (FS) correlated well with ejection fraction (EF) on exercise (r = 0.79, P = less than 0.001). There was also a good correlation between changes in global function from rest to exercise (r = 0.82, P = less than 0.001) with a sensitivity of diagnosing CAD of 71% and specificity of 80%. New regional wall abnormalities were detected in 25/28 with CAD with a sensitivity of 89% and specificity of 60%. There was also a close correlation between mean diameters measured with gated MIBI scans and volumes measured with RNV, end-diastolic diameter (EDD) versus end-diastolic volume (EDV) r = 0.78 (P = less than 0.001) at rest and r = 0.74 (P = less than 0.001) on exercise and end-systolic diameter (ESD) versus end-systolic volume (ESV) r = 0.72 (P = less than 0.001) at rest and r = 0.72 (P = less than 0.001) on exercise. This produced a sensitivity for detecting CAD of 79% and a specificity of 73%. These results show that gated MIBI scanning on exercise provides information comparable to RNV so enhancing the diagnostic usefulness of MIBI.

Gated technetium-99m methoxy-isobutylisonitrile perfusion imaging

Technetium-99m methoxy-isobutylisonitrile, has been shown to be a useful perfusion agent for detecting coronary artery disease. Gated acquisition of perfusion images may remove motion artefact and improve detection. We compared the results of sensitivity and specificity for detecting coronary artery disease using perfusion images from the whole cardiac cycle (ungated) or from end-diastolic (gated) frames in 46 subjects, 31 with significant coronary disease and 15 with normal coronary arteries. There was no significant difference in detection of patients with coronary disease between the ungated and end-diastolic images: 25 31 with the ungated image and 28 31 with the end-diastolic. An improvement was made in detecting defects in the left anterior descending artery territory: 17 20 with the end-diastolic vs 11 20 with the ungated image ( P < 0.05) and in the right coronary artery region: 16 21 vs 10 21 ( P < 0.05), with an overall improvement in detecting regions supplied by stenosed coronary arteries: 45 55 end-diastolic vs 31 55 ungated ( P < 0.01). These results suggest use of the end-diastolic frame can significantly enhance the diagnostic capacity of methoxy-isobutylisonitrile perfusion imaging.

Comparison of neutral and cationic myocardial perfusion agents: Characteristics of accumulation in cultured cells

Uptake and washout kinetics of two new neutral lipophilic technetium-99m-labeled boronic acid adducts of technetium tris(dioxime) (BATO complexes) were studied in monolayers of contractile chick heart cells and compared to the cationic myocardial perfusion agents, 99mTc(CNCH 2C(CH 3) 2OCH 3) + 6 (Tc-MIBI) and 201Tl +. 99mTcCl(CDOH) 2(CDO)(BCH 3), where CDO = cyclohexanedione dioxime (CDO-MeB), had a 7-fold greater net accumulation than Tc-MIBI and the most rapid unidirectional washout with a fast initial phase and a slower secondary component. Incubation with cationic membrane transport inhibitors or metabolic inhibitors had little or modest influence, respectively, on uptake of these BATO complexes. Studies with NIH 3T3 fibroblasts indicated that the neutral complexes did not show myocyte specific accumulation.

Gated 99Tcm-cm-MIBI myocardial function imaging

The introduction of the 99Tcm isonitrile perfusion agents has provided improved myocardial image quality with conventional imaging equipment allowing improved edge definition on gating. We evaluated left ventricular wall motion in 46 patients using gated 99Tcm-2-methoxy-2-methyl-isopropyl-1-isonitrile (MIBI) scintigraphy. Using a method of myocardial profiles in four axes, global and regional fractional shortening (FS) were assessed. A good correlation was found between FS in the left anterior oblique (LAO) 40 degrees projection and ejection fraction (EF) on gated radionuclide ventriculography (r = 0.81, P less than 0.001). This was improved by using FS in two planes, LAO 40 degrees and anterior (r = 0.88, P less than 0.001). There was also a good correlation between FS in two planes and EF on cine-angiography (r = 0.72, P less than 0.001). There was good intra- and interobserver agreement with the studies. Assessment of myocardial function using gated MIBI imaging and myocardial profiles provides useful additional information to the perfusion scan, thus enhancing the diagnostic usefulness of the agent.

Single-photon emission computed tomographic thallium imaging with adenosine, dipyridamole, and exercise

Strees thallium imaging is a sensitive technique for detecting coronary artery disease, particularly in those patients with multivessel disease. Single-photon emission computed tomography (SPECT) is superior to planar imaging; because of improved image quality and lack of overlap between normal and abnormal segments, SPECT has greater ability to detect diseased arteries. The inherent three-dimensional nature of the data presentation suggests the feasibility of quantifying the extent of myocardium at risk. Pharmacologic stressors such as adenosine and dipyridamole allow imaging with thallium (and probably other perfusion agents) even in patients who are not candidates for exercise testing or who cannot achieve adequate levels of exercise. Studies suggest that adenosine has unique advantages for use with SPECT perfusion imaging with a high degree of accuracy. In our experience the sensitivity of detecting one-vessel disease is higher with adenosine-thallium imaging than in exercise SPECT thallium imaging. The degree of cononary hyperemia is greater and the duration of action is shorter with adenosine than with dipyridamole.

Physiological basis of myocardial perfusion imaging with the technetium 99m agents

In recent years, several technetium 99m-labeled myocardial perfusion agents have been under investigation to determine their utility in assessing regional myocardial blood flow and cellular viability. 99mTc sestamibi (2-methoxyisobutyl isonitrile), one of the most promising of these agents, is a lipophilic cation that is sequestered largely within mitochondria by the large negative transmembrane potential. Experimental studies have shown that this agent is taken up in the myocardium in proportion to blood flow, but like other diffusible radionuclides underestimates flow at high flow rates. Fractional extraction (Emax) for 99mTc sestamibi is lower than that for thallium 201, but net myocardial uptake is comparable between the two radionuclides. Compared with 201Tl, 99mTc sestamibi does not significantly redistribute. Studies have shown that 99mTc sestamibi uptake after reperfusion, preceded by varying periods of coronary occlusion, reflects the degree of myocardial salvage and viability. 99mTc teboroxime, another promising new perfusion agent, is a boronic acid adduct of technetium dioxime complexes. Emax of 99mTc teboroxime is higher than Emax for 201Tl, but myocardial washout is very rapid (half-life = 21 minutes). Myocardial uptake is proportional to regional flow as found with 99mTc sestamibi and 201Tl.

Assessment of the extent of jeopardized myocardium during acute coronary artery occlusion followed by reperfusion in man using technetium-99m isonitrile imaging

We tested the feasibility of technetium-99m methoxyisobutyl isonitrile (Tc-MIBI) imaging for delineating jeopardized myocardium during acute coronary occlusion and reperfusion in man. This new perfusion agent was injected in 25 patients during elective percutaneous transluminal coronary angioplasty (PTCA) of a single-vessel left anterior descending (LAD) coronary artery stenosis. Distinct perfusion defects were present on “occlusion” images but not on “open vessel” images obtained 20 to 24 hours later in 21 patients (84%). The extent and severity of perfusion defects were significantly smaller in patients with distal versus proximal LAD occlusions (3.4 ± 1.2 versus 5.2 ± 1.5 segments; p < 0.001). The only factor that was significantly related to the presence or absence of such “ischemic” perfusion defects was the absence or presence of visible collateral vessels to the LAD ( p < 0.03). The site of occlusion, presence of wall motion abnormalities, or occlusion time did not influence the results significantly. Thus the myocardial area at risk could be visualized and quantitated by Tc-MIBI imaging even after occlusion times as short as 15 seconds, but functioning collateral vessels are capable of protecting jeopardized myocardium in this setting.

Comparison between exercise myocardial perfusion and wall motion using 201 T1 and 191 Irm simultaneously

By exploiting the ultrashort half-life 191Irm as tracer for left ventricular first-pass angiocardiography and 201Tl as myocardial perfusion agent, direct comparison between myocardial perfusion and regional wall motion was obtained during the same exercise stress test in patients with non-significant coronary artery disease, in patients with recent myocardial infarction, and in patients six weeks after successful percutaneous transluminal coronary angioplasty (PTCA). A good agreement between regional myocardial perfusion and regional wall motion was observed in patients with non-significant coronary artery disease and in most patients with recent myocardial infarction. In contrast, discrepancies occurred at maximal exercise in patients studied six weeks after successful PTCA: only 38% of the patients with no evidence of restenosis and with a completely normal myocardial perfusion scintigraphy had a normal regional wall motion at maximal exercise stress. According to these results, a normal uptake of 201Tl six weeks after PTCA would mean that the circulation has been successfully reestablished but without predicting the functional capacities of the myocardial cells which remain altered at least six weeks after the revascularization procedure in about two-thirds of the patients. We conclude that 191Irm in combination with 201Tl offers the opportunity of performing myocardial perfusion and wall motion studies simultaneously both at rest and during exercise.

99Tcm-SESTAMIBI for planar myocardial perfusion imaging; not as ideal as the physical properties

99Tcm-methoxyisobutyl isonitrile (Tc-SESTAMIBI) has recently been introduced as a new myocardial perfusion agent which exhibits ideal physical properties for imaging with the gamma camera. To assess the diagnostic accuracy of planar Tc-SESTAMIBI, myocardial perfusion imaging was performed in 60 consecutive patients at rest and during exercise. The results were compared with coronary angiographic findings, obtained within 3 months of the exercise test. Planar 201Tl images were also performed on the same day and to the same level of stress as the Tc-SESTAMIBI exercise. Exact segmental agreement between Tc-SESTAMIBI and 201Tl was 77%. Nineteen per cent of all 900 segments demonstrated ischaemia with Tc-SESTAMIBI and 20% with 201Tl. The overall sensitivity for detecting haemodynamically significant coronary artery disease with Tc-SESTAMIBI was 86% and specificity was 78%; with 201Tl the values were 89 and 78%, respectively (differences not significant). Vessel-specific comparative detection rates revealed no statistical significant differences between both radiopharmaceuticals. Intra-observer variability for Tc-SESTAMIBI images was 12% and for 201Tl it was 14%. Inter-observer variability for Tc-SESTAMIBI was 14% and for 201Tl 17%. Although the physical characteristics of Tc-SESTAMIBI allow crisp and clear high-count density imaging, no significant differences are found when planar images are compared with 201Tl and are well within observer variabilities.

Myocardial perfusion imaging with technetium-99m-labeled agents

Thallium-201 (201Tl) is suboptimal as a single-photon emitting agent for myocardial perfusion imaging, in view of its low-energy photons and long half-life. To circumvent these limitations, two new myocardial perfusion imaging agents labeled with technetium-99m (99mTc) have been developed. They are Tc-sestamibi and Tc-teboroxime. Clinical trials of myocardial perfusion with both tracers have shown results similar to those obtained with 201Tl for detection of coronary artery disease. Results to date indicate that Tc-sestamibi accurately detects and locates myocardial infarction and can accurately assess both left and right ventricular ejection fractions by the first-pass technique. In addition, research has shown that rest-stress studies can be performed on the same day and that Tc-sestamibi can be used to assess the results of thrombolytic therapy. Tc-teboroxime has excellent myocardial tracer uptake characteristics but is cleared very rapidly from the myocardium. These features make Tc-teboroxime well suited to rapid serial studies. These new technetium myocardial perfusion agents have just become available for routine clinical use and are likely to replace 201Tl in many of its clinical applications.

Regional distribution study of brain perfusion and metabolic agents in normal and tumour bearing rat brains using autoradiographic technique

Regional distribution of brain perfusion imaging agents, [ 131I] N,N,N′-trimethyl- N′-[2-hydroxy-3-methyl-5-iodobenzyl]1,3 propanediamine (HIPDM) and [ 131I] N-isopropyl- p-iodoamphetamine (IMP), was compared with the distribution of patterns of [ 14C] l-methionine and [ 14C] d-glucose in normal and tumour bearing rat brains using autoradiographic technique. There was higher concentration of the radiopharmaceutical in grey than white matter in normal rat brain. Autoradiographs of brain tumour sections showed very low uptake of [ 131I]HIPDM and [ 131I]IMP as compared to normal brain tissue. There was moderate concentration of [ 14C] d-glucose and avid uptake of [ 14C] l-methionine in tumours. Autoradiographic study is useful for evaluating distribution patterns of radiopharmaceuticals.

Performance of a single crystal digital gamma camera for first pass cardiac studies

First pass radionuclide angiocardiography (FPRNA) has gained increasing interest because of the development of new 99Tcm-labelled perfusion agents and of new 191Os/191Irm generator systems. The aim of the study was to evaluate the performance capacities of a small field of view single crystal digital gamma camera for 99Tcm and 191Irm at high count rates. The camera dead time for 99Tcm (window 30%) was well corrected up to 300 kcps in fast acquisition mode using the relative decrease of a small shielded reference source. Using the decaying activity method for 191Irm the non-linearity response of the gamma camera was corrected by an 191Os reference soruce up to 210 kcps at 70 keV, 75 kcps at 129 keV and 320 kcps including both peaks. Saturation count rates were respectively 270 kcps, 150 kcps and 420 kcps and high count rate resolution (FWHM) 9.0, 7.3 and 10.3 mm. Since the accuracy of first pass measurements is more sensitive to count rate than to spatial resolution the 50-150 keV window was chosen for clinical studies. In data obtained from 32 ECG gated FPRNA patient studies, the whole field of view count rate during the left ventricular phase ranged from 100 to 250 kcps with 80 to 120 mCi (2960-4400 MBq) of 191Irm and 100 to 180 kcps with 20 to 25 mCi (750-925 MBq) of 99Tcm red blood cells permitting for both tracers accurate non-linearity correction.

Chloro → hydroxy substitution on technetium BATO [TcCl(dioxime) 3BR] complexes

The neutral, seven coordinate complexes of technetium known as the BATO ( B oronic acid A dducts of T echnetium di O ximes) complexes have shown their utility as myocardial and cerebral perfusion agents. The axial chloride ligand of the BATO complexes [ 99mTcCl(dioxime) 3BR]is labile to substitution by a competitive anion; under physiological conditions, the axial chloride ligand can be replaced by a hydroxy group. The chloro and hydroxy analogs have different biodistributions and single-pass cerebral extraction efficiencies. The influence of structure on the rate of the in vitro chloro/hydroxy exchange process has been studied. The mechanism of axial ligand exchange was found to be S NI-CB, which proceeds by way of a transient, neutral six coordinate complex. Evidence is presented which indicates that chloro/hydroxy exchange is not the mechanism by which BATO complexes are retained in the brain.