Background —The exercise treadmill test (ETT) and Tl201 single proton emission computed tomography (SPECT) are of short- to medium-term prognostic value in coronary heart disease. We assessed the long-term prognostic value of these tests in a large population of patients with low- to intermediate risk of cardiac events. Methods and Results —One thousand one hundred thirty-seven patients (857 men, age 55±9 years) referred for typical (62.1%) or atypical (22.4%) chest pain, or suspected silent ischemia (15.5%), were followed up for 72±18 months. Overall mortality was higher after strongly positive (ST depression >2 mm, or >1 mm for a workload ≤75 W) (2.36%/y) or nondiagnostic ETT (1.63%/y) than after normal (0.85%/y) or positive ETT (1.37%/y) ( P =0.002), and after abnormal SPECT than after normal SPECT (1.60%/y versus 0.68%/y, P =0.001). The major cardiac event rate (cardiac death or myocardial infarction [MI]) was 0.88%, 1.59%, 2.10%, and 2.13%/y after negative, positive, strongly positive, and nondiagnostic ETT, respectively ( P =0.003), and 0.56%, 1.43%, and 2.05%/y in patients with 0, 1 to 2, and ≥3 abnormal segments on SPECT, respectively ( P <0.002). An abnormal SPECT was predictive of MI ( P <0.001), whereas ETT was not. In multivariate analysis, SPECT was of incremental prognostic value over clinical and ETT data for predicting overall mortality and major cardiac events. Conclusions —The incremental predictive value of SPECT is maintained over 6 years and is particularly relevant after positive, strongly positive, and nondiagnostic ETT.

BACKGROUND:The exercise treadmill test (ETT) and Tl201 single proton emission computed tomography (SPECT) are of short- to medium-term prognostic value in coronary heart disease. We assessed the long-term prognostic value of these tests in a large population of patients with low- to intermediate risk of cardiac events. METHODS AND RESULTS:One thousand one hundred thirty-seven patients (857 men, age 55+/-9 years) referred for typical (62.1%) or atypical (22.4%) chest pain, or suspected silent ischemia (15.5%), were followed up for 72+/-18 months. Overall mortality was higher after strongly positive (ST depression >2 mm, or >1 mm for a workload =75 W) (2. 36%/y) or nondiagnostic ETT (1.63%/y) than after normal (0.85%/y) or positive ETT (1.37%/y) (P=0.002), and after abnormal SPECT than after normal SPECT (1.60%/y versus 0.68%/y, P=0.001). The major cardiac event rate (cardiac death or myocardial infarction [MI]) was 0.88%, 1.59%, 2.10%, and 2.13%/y after negative, positive, strongly positive, and nondiagnostic ETT, respectively (P=0.003), and 0.56%, 1.43%, and 2.05%/y in patients with 0, 1 to 2, and >/=3 abnormal segments on SPECT, respectively (P<0.002). An abnormal SPECT was predictive of MI (P<0.001), whereas ETT was not. In multivariate analysis, SPECT was of incremental prognostic value over clinical and ETT data for predicting overall mortality and major cardiac events. CONCLUSIONS:The incremental predictive value of SPECT is maintained over 6 years and is particularly relevant after positive, strongly positive, and nondiagnostic ETT.

BACKGROUND:Bis[N-ethoxy,N-ethyl(dithiocarbamato)]nitrido Tc (V) (TcN-NOET) is a new technetium complex proposed as a tracer of myocardial perfusion. However, its cellular uptake mechanisms are unknown, although membrane localization on rat heart preparations and preferential binding to polymorphonuclear neutrophils (PMNs) have been reported. Because of the central role of calcium in PMN actions, a relationship was hypothesized between this ion flux and TcN-NOET cellular uptake.METHODS AND RESULTS:The mechanisms of cellular uptake of TcN-NOET were investigated in newborn rat cardiomyocytes by study of the effect of calcium channel modulators on tracer binding. Nifedipine had no effect on tracer uptake at 1 minute. However, verapamil 0.1 micromol/L and diltiazem 0.5 micromol/L induced a 40% decrease in uptake. Conversely, Bay K 8644 0.25 micromol/L increased TcN-NOET uptake by 73%. Alterations in other membrane ion transports failed to modify tracer uptake, indicating the specificity of the relationship between TcN-NOET uptake and calcium channels. Kinetic studies indicated that cellular net accumulation of the tracer was slow (t1/2=28.5 minutes) and retention was prolonged (84% of initial activity retained after 120 minutes of washout). The energy dependence of TcN-NOET uptake was investigated after 60 minutes of metabolic inhibition by iodoacetic acid plus rotenone. The ATP decrease was not associated with reduction in tracer uptake at 1 minute (114.9+/-21.9% of control, P=NS).CONCLUSIONS:The decrease in uptake observed with verapamil and diltiazem, the increase with Bay K 8644, and the lack of effect with nifedipine suggest that TcN-NOET binds to L-type calcium channels in the open configuration, without entering cardiomyocytes. The kinetics of TcN-NOET accumulation and retention are slow, and the mechanism for cellular uptake is not energy-dependent. From a clinical point of view, the effect of concurrent treatment by calcium inhibitors on myocardial binding of TcN-NOET should be taken into account.

6-deoxy-6-iodo-D-glucose (6-DIG) was rapidly taken up by adipocytes. Insulin increased 6-DIG transport in adipocytes isolated from both rats and mice. This stimulation was more important in rat than in mouse adipocytes, in agreement with their respective amount of Glut 4 transporters. In two insulin resistant states, the biological behavior of 6-DIG and 3-O-methyl-D-glucose was similar. These results indicated that 6-DIG, which was transported into the cells via the glucose transporters, could be potentially useful to measure modifications of glucose transport.

Two anomeric analogues of glucose labelled with 123 iodine in position 6, proposed as tracers of glucose transport in vivo, have been synthesized: alpha- and beta-methyl-6-deoxy-6-iodo-D-glucopyranoside (alpha MDIG and beta MDIG). The aim of this study was to determine whether these molecules interact with the glucose transporter and whether they could be used as tracers of glucose transport in vivo. The biodistribution of alpha MDIG and beta MDIG was studied in the mouse in vivo. To determine if these two anomers enter the cell via the glucose transporter, their uptake was measured in isolated perfused rat hearts, in human erythrocytes in suspension, and in cardiomyocytes of neonatal rat in culture. Both alpha MDIG and beta MDIG had similar repartitions in the mouse: myocardial uptake averaged 7% of the injected dose/g of organ at 2 min postinjection and alpha MDIG competed with D-glucose to enter the cells. Insulin produced a 123% increase of its uptake in isolated perfused rat hearts and a 100% increase in cardiomyocytes of neonatal rat in culture. alpha MDIG uptake was lowered in the presence of glucose transport inhibitors in each experimental model. An interaction between beta MDIG and glucose transporters was observed only in human erythrocytes in suspension. Only alpha MDIG interacts with the glucose transporter, and thus could be used to estimate glucose transport in vivo.

A glucose analogue labelled with iodine-123 in position 6 has been synthesized: [123I]-6-deoxy-6-iodo-D-glucose (6DIG). The aim of this study was to examine its biological behaviour in order to assess whether it could be used to evaluate glucose transport with SPECT. To establish whether 6DIG enters the cells using the glucose transporter, four biological models have been used: human erythrocytes in suspension, neonatal rat cardiomyocytes in culture, isolated perfused rat hearts, and biodistribution in mice. 6DIG competed with D-glucose to enter the cells and its entry was increased by insulin and inhibited in the presence of cytochalasin B. The biological behaviour of 6DIG was similar to that of 3-O-methyl-D-glucose. 6DIG is a tracer of glucose transport which is very promising for clinical studies.

The best test presently available to ascertain residual viability within an infarct-related area involves the use of fluorine-18 fluorodeoxyglucose (FDG) to detect the persistence of some cellular metabolism. Rest reinjection of thallium-201 is a less accurate alternative but is easy to perform. Iodinated fatty acids, which are used with standard gamma cameras, are proposed as markers of cellular metabolism. This study was performed to assess the value of 16-iodo-3-methyl-hexadecanoic acid (MIHA) as a marker of the residual cellular metabolism by comparison with FDG in patients with a recent myocardial infarction, and to evaluate its contribution compared with the201Tl stress-redistribution-reinjection technique. Stress-redistribution-reinjection201T1 imaging, rest MIHA imaging and glucoseloaded FDG imaging were performed in 22 patients with recent myocardial infarction. Out of the 628 myocardial segments obtained from the left ventricular analysis, 400 were hypoperfused (relative uptake <0.75 of maximum uptake on stress201T1 imaging), 177 of which were severely hypoperfused (relative uptake <0.50). Receiver operating characteristic (ROC) curves for predicting metabolic myocardial viability with FDG were derived from the results in respect of (a)201T1 activity during exercise, redistribution and reinjection and (b) MIHA up-take, using the two FDG thresholds most commonly considered to define metabolic viability (0.50 and 0.60). Analysis of the 400 hypoperfused segments demonstrated that201T1 reinjection was the most accurate test in predicting the presence of myocardial viability (area under the ROI curves=0.85 and 0.86 at the 0.50 and 0.60 FDG thresholds, respectively;P<0.05 vs other tests). The global predictive values of MIHA and201T1 reinjection were, respectively, 0.87 and 0.89 at the 0.50 FDG threshold (NS), and 0.82 and 0.87 at the 0.60 FDG threshold (NS). When only the 177 severely hypoperfused segments were considered,201T1 reinjection remained the most accurate test (accuracy 0.84 at the 0.50 FDG threshold and 0.82 at the 0.60 FDG threshold), while the accuracy of MIHA decreased significantly (0.78 at the 0.50 FDG threshold and 0.73 at the 0.60 FDG threshold,P<0.05 vs201T1 reinjection). In all circumstances, MIHA was less specific than201T1 reinjection for the detection of metabolic viability. In conclusion, in patients with recent myocardial infarction, MIHA accurately detects the persistence of metabolic viability, but is not superior to201T1.

La synthèse de tétramines cycliques, de tétramines cycliques mono-et tétra-N-alkylées est développée ainsi que la complexation due technétium par ces ligands à partir de 99mTcO−4. Plusieurs réducteurs du pertechnétate sont étudiés ainsi que le rendement de complexation, la charge et la lipophilie des complexes. Leur étude biologique chez la souris (biodistribution) et chez le chien (scintigraphie) a permis de mettre en évidence une excellente captation hépatobiliaire du trans-99mTcO2(1-dodécyl-1,4,8,11-tétraazacylotétradécane).

Analogues of glucose labeled with 123 iodine in positions 1, 2 or 3 have been synthesized. The aim of this study was to examine their biological behavior in four experimental models in order to assess whether they could be used to evaluate the uptake of glucose with single photon emission computed tomography (SPECT). The results obtained have shown that none of these molecules enters the cell using the glucose transporter. Therefore, they cannot be used as tracers of glucose uptake.

For an iodinated analogue of glucose to be useful for evaluating glucose uptake using single-photon emission computed tomography (SPECT), it must enter the cell via the same transporter as glucose and accumulate within the cell without being degraded. The biological behavior of the iodinated tracer must therefore be similar to that of 2-deoxy-d-[1-14C]-glucose (2-DG). In the present study, four experimental models (biodistribution in mouse, isolated rat heart, human erythrocytes in suspension and cultured neonatal rat cardiomyocytes) have been chosen and protocols have been set up which allow for the examination of small quantities of iodinated analogues of glucose. The uptakes of 2-DG and of l-[1-14C]-glucose have been measured in these models to establish reference values which will be compared with uptake values for iodinated analogues of glucose.

Wecompared TcN-NOET (t@s(N-ethoxy, N-eth@1 d@carbam ato)nftrido @Fc@ and @°i1 imagesto estimatethe utilityof this compoundin the detectionof coronaryartery disease (CAD). Methods: Twenty-five patientsundergoingcardiaccatheterize lion had atress-redisbibution-ralnjection @°@11 SPECTimaging, stress-delayed(2, 4 and 6 hr postinjection) and rest-delayed(4 hrpostinjection) TCN-NOET SPECTimaging.Results: Ninateen

UNLABELLED:[Bis (N-etoxy, N ethyl dithiocarbamato) nitrido] 99mTc (V) (TcN-NOET) is a new neutral lipophilic myocardial imaging agent proposed for clinical use for detecting coronary artery disease. We studied the relation between myocardial retention of TcN-NOET and myocardial blood flow (MBF) in a canine model.METHODS:A wide range of MBF was induced by partial regional coronary occlusion and dipyridamole infusion (protocols 1,2 and 3). Myocardial activity of TcN-NOET was determined by in vitro tissue counting at 15 or 90 min postinjection. Tracer activity was correlated with radiolabeled microspheres using linear regression analysis.RESULTS:There was a linear correlation between myocardial TcN-NOET activity and microspheres in protocol 1 (r = 094, 15 min postinjection, protocol 2 (r = 0.94, 15 min postinjection after dipyridamole) and protocol 3 (r = 0.91, 90 min postinjection after dipyridamole). When arterial occlusion was discontinued (protocol 4), there was no longer a close linear correlation (r = 0.26). The first-pass myocardial extraction action of TcN-NOET was 75.5% +/- 4% under basal conditions and 85% +/- 2% under hyperemic conditions (p < 0.01).CONCLUSION:Up to 90 min after injection, the relationship between TcN-NOET myocardial retention and blood flow is excellent over a wide range of flows. After reflow, TcN-NOET redistributes almost completely within 90 min.

UNLABELLED We compared TcN-NOET [bis(N-ethoxy, N-ethyl dithiocarbamato)nitrido 99mTc] and 201Tl images to estimate the utility of this compound in the detection of coronary artery disease (CAD). METHODS Twenty-five patients undergoing cardiac catheterization had stress-redistribution-reinjection 201Tl SPECT imaging, stress-delayed (2, 4 and 6 hr postinjection) and rest-delayed (4 hr postinjection) TcN-NOET SPECT imaging. RESULTS Nineteen patients had coronary stenosis > or = 50% and six were normal. Stress TcN-NOET and 201Tl imaging were concordant for the presence of CAD in 22/25 patients (88%, kappa = 0.76 +/- 0.20). The overall sensitivity of TcN-NOET SPECT imaging was 74% (14/19 patients) and 68% (13/19 patients) for 201Tl SPECT imaging. The specificity was 100% (6/6 patients) for both techniques. The overall agreement of TcN-NOET and 201Tl for the presence of disease in individual coronary arteries was 96% (72/75 arteries, kappa = 0.92 +/- 0.16). Segmental analysis of stress images showed a concordance in 211/225 segments (94%, kappa = 0.82 +/- 0.09). Comparison of the 4-hr images showed a concordance between 201Tl and TcN-NOET in 21/23 patients. Following TcN-NOET injection at rest, seven patients had a defect on the initial images, which had normalized 4 hr postinjection in four patients (57%). CONCLUSION Perfusion imaging with TcN-NOET and 201Tl gives comparable diagnostic information in patients undergoing exercise testing for assessment of CAD. Because of the normalization of myocardial activity 4 hr after injection in some patients, we conclude that TcN-NOET is a potential technetium compound equivalent to 201Tl.

UNLABELLEDThe synthesis and biodistribution in various animal models (rat, dog, pig and monkey) of 99mTc radiopharmaceuticals containing the Tc = N multiple bond are reported.METHODSThe complexes are represented by the general formula 99mTcN(L)2, where L is the monoanionic form of a dithiocarbamate ligand of the type [R1(R2)-N-C(=S)S]-, and R1 and R2 are variable, lateral groups. The preparations were carried out, both as a liquid and freeze-dried formulation, through a simple procedure involving the initial reaction of [99mTcO4]- with S-methyl N-methyl dithiocarbazate [H2NN(CH3)C(=S)SCH3], in the presence of tertiary phosphines or Sn2+ ion as reductants, followed by the addition of the sodium salt of the ligand (NaL) to afford the final product. The chemical identity of the resulting complexes was determined by comparing their chromatographic properties with those of the corresponding 99Tc analogs characterized by spectroscopic and x-ray crystallographic methods. The complexes are neutral and possess a distorted, square pyramidal geometry.RESULTSNo decomposition of the complexes, in physiological solution, was observed over a period of 6 hr. Imaging and biodistribution studies demonstrated that these radiopharmaceuticals localize selectively in the myocardium of rats, dogs and primates, but that they failed to visualize the pig heart. The kinetics of heart uptake and clearance were studied in rats and dogs, and found to be strongly influenced by variation of the lateral R1 and R2 groups.CONCLUSIONThe high quality of myocardial images obtained in dogs and monkeys demonstrates that the derivative 99mTcN[E-t(EtO)NCS2]2 [99mTcN(NOEt)] exhibits the most favorable distribution properties for further studies in humans.