New diketopiperazines as vectors for peptide protection and brain delivery: Synthesis and biological evaluation.

New strategies allowing the transfer of molecules, especially peptides, through the blood-brain barriers are a major pharmacological challenge for the treatment of brain diseases. The present study aims at evaluating in vivo the cerebral bioavailability of carrier systems, based on small and functionalizable 2,5-diketopiperazine (DKP) motifs. We studied 2 different cyclo(Lys-Lys) DKP scaffolds alone and a cyclo(Lys-Gly) DKP carrier bearing as peptide model, the tau protein hexapeptide VQIVYK sequence. The different carrier systems were synthesized and radiolabeled using one of the free domains. The stability, biodistribution, and ability to cross blood-brain barrier were investigated in vivo in mice for 99m Tc-DKP scaffolds, 99m Tc-HVQIVYK peptide alone, and 99m Tc-DKP-VQIVYK. 125 I-labelled bovine serum albumin was used as negative control for brain uptake. Both radiolabeled DKPs scaffolds and 99m Tc-DKP-VQIVYK showed a high stability, while peptide 99m Tc-HVQIVYK alone was quickly degraded in vivo. The presence of 99m Tc-DKPs scaffolds and 99m Tc-DKP-VQIVYK was observed in the ventricular and subarachnoid spaces and to a lower extent in the brain parenchyma up to 45 minutes post-injection in mice. This work highlights the potentiality of DKP scaffolds as vectors to transport peptides into the brain by limiting proteolysis and favoring cerebral bioavailability.

Targeted radionuclide therapy with RAFT-RGD radiolabelled with (90)Y or (177)Lu in a mouse model of αvß3-expressing tumours.

PURPOSE: The αvß3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvß3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with ß(-) emitters in a nude mouse model of αvß3 integrin-expressing tumours. METHODS: Biodistribution and SPECT/CT imaging studies were performed after injection of (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvß3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD and (90)Y-RAFT-RAD or (177)Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvß3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvß3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. RESULTS: Injection of 37 MBq of (90)Y-RAFT-RGD into mice with large αvß3-positive tumours or 37 MBq of (177)Lu-RAFT-RGD into mice with small αvß3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of (90)Y-RAFT-RAD or 37 MBq of (177)Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of (90)Y-RAFT-RGD had no effect on the growth of αvß3-negative tumours. CONCLUSION: (90)Y-RAFT-RGD and (177)Lu-RAFT-RGD are potent agents targeting αvß3-expressing tumours for internal targeted radiotherapy.

Pre-clinical and clinical evaluation of nuclear tracers for the molecular imaging of vulnerable atherosclerosis: an overview.

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerotic plaques in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could allow the identification of vulnerable patients by non-invasive in vivo scintigraphic imaging following administration of a radiolabeled tracer. The purpose of this review is to provide an overview of radiotracers that have been recently evaluated for the detection of vulnerable plaques together with the biological rationale that initiated their development. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable plaques in carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of coronary arteries remains challenging, mostly because of their small size and their vicinity with unbound circulating tracer. The experimental and pilot clinical studies reviewed in the present paper represent a fundamental step prior to the evaluation of the efficacy of any selected tracer for the early, non-invasive detection of vulnerable patients.

First human treatment of resistant neoplastic meningitis by intrathecal administration of MTX plus (125)IUdR.

PURPOSE: Neoplastic meningitis is often the final outcome of disseminated cancer and is rapidly lethal. Its limited treatment relies on systemic or intrathecal chemotherapy with methotrexate (MTX) or thiotepa. When 5-iodo-2'-deoxyuridine labeled with (125)I ((125)IUdR) is incorporated into the DNA of mitotic tumor cells, the Auger electrons emitted during iodine decay are highly cytotoxic. The radiotherapeutic efficacy of (125)IUdR administered intrathecally has also been established in animals bearing spinal cord tumors, and MTX is known to potentiate the response. This approach has not been tested in the clinic. METHODS: A 44-year-old woman, with locally advanced pancreatic cancer, was treated for three years with complete systemic remission, but then relapsed with cytologically proven neoplastic meningitis. The patient was given four successive intrathecal injections of MTX (10 mg) every 12 h and, with the fourth dose, 1850 MBq (125)IUdR, followed by four additional MTX doses. The response was monitored by cytology and CA19.9 (carbohydrate antigen 19.9) levels in the cerebrospinal fluid (CSF) as well as by clinical status of the patient. RESULTS: The follow-up of cytology and CA19.9 levels in the CSF showed dramatic improvement within 26 days followed by a biological relapse on Day +36. There was no evidence of local central nervous system toxicity. Three months later, neoplastic meningitis recurred and meningeal tumor infiltration was observed on magnetic resonance imaging. Six months after MTX-(125)IUdR treatment, the patient died. CONCLUSION: (125)IUdR treatment proved to be feasible without acute neurological toxicity and seemed to have produced a biological response. This attempt provides the basis for designing prospective clinical trials.

Mapping of brain tissue hematocrit in glioma and acute stroke using a dual autoradiography approach.

Hematocrit (Hct) determines the ability of blood to carry oxygen. While changes in systemic Hct are known to impact stroke or tumor control, changes in local (tissue) Hct (tHct) induced by these diseases have however received little attention. In this study, we evaluate tHct in acute stroke and in glioma models using a new approach to map tHct across the brain, a dual isotope autoradiography, based on injections of 125I-labeled albumin and 99mTc-lalbeled red blood cells in the same animal. For validation purpose, tHct was mapped in the rat brain (i) under physiological conditions, (ii) following erythropoietin injection, and (iii) following hemodilution. Then, tHct was then mapped in stroke (middle cerebral artery occlusion) and tumor models (9LGS and C6). The mean tHct values observed in healthy brains (tHct = 29 ± 1.3%), were modified as expected by erythropoietin (tHct = 36.7 ± 2.6%) and hemodilution (tHct = 24.2 ± 2.4%). Using the proposed method, we observed a local reduction, spatially heterogeneous, in tHct following acute stroke (tHct = 19.5 ± 2.5%) and in both glioma models (9LGS: tHct = 18.5 ± 2.3%, C6: tHct = 16.1 ± 1.2%). This reduction and this heterogeneity in tHct observed in stroke and glioma raises methodological issues in perfusion imaging techniques where tHct is generally overlooked and could impact therapeutic strategies.

Effects of a myocardial ischaemia-guided therapeutic program on survival and incidence of coronary events in asymptomatic patients with diabetes: the ARCADIA study.

AIM: To assess the prognostic impact of a therapeutic program based on bioclinical risk-stratification and myocardial-perfusion-imaging (MPI) data on survival and the occurrence of coronary events (CE=death+myocardial infarction) in asymptomatic patients with diabetes. METHOD: Five hundred twenty one consecutive asymptomatic diabetic outpatients were prospectively enrolled and clinically classified as being at either low or high cardiac risk. All high-risk patients (n=245, age 61+/-9 years) underwent MPI and an intensive multifactorial medical therapeutic program, including anti-ischaemic agents in cases of moderate ischemia; a coronary angiography was performed in all high-risk patients with severe ischaemia (n=38), followed by immediate revascularization if necessary (n=21). Low-risk patients (n=276, age 57+/-9 years) underwent medical management of their risk factors. RESULTS: At the 19-month (median) follow-up (range, 12-36 months), both high- and low-risk patients showed similarly low CE rates (2.3% and 1.5% per year, respectively; age- and gender-adjusted log-rank P=NS). None of the patients who underwent myocardial revascularization experienced any CEs, and none of the low-risk patients died during follow-up. The negative predictive value of first-line bioclinical stratification was 0.98 for the occurrence of CEs, and 0.95 when low-risk patients were combined with high-risk patients who had normal MPI findings. CONCLUSIONS: Bioclinical first-line stratification allows identification of diabetic patients who have a good medium-term cardiac prognosis. The CE rate is similar in selected high-risk asymptomatic patients with diabetes using an intensive MPI-guided program that combines medical therapy, coronary angiography in the 16% of cases with severe ischemia and, if appropriate, revascularization.

[Study of a detection strategy for silent ischemia in diabetic patients: 18 month follow-up of the ARCADIA register]. / Etude d'une stratégie de détection de l'ischémie silencieuse chez les patients diabétiques: suivi à 18 mois du registre ARCADIA.

BACKGROUND: The prognostic impact of a myocardial ischemia-based therapeutic program in asymptomatic diabetic patients remains controversial. We prospectively assessed the benefit of a stratification algorithm based upon clinical and myocardial perfusion imaging (MPI) data on cardiovascular events in such patients in a non-randomized register. METHOD: 701 consecutive asymptomatic diabetic patients were classified to be at low or intermediate-to-high cardiac risk according to 13 simple boil-clinical parameters. Intermediate-to-high risk patients were scheduled for MPI and underwent either a conventional (Group 1, n=180) or an intensive multifactorial (Group 2, n=245) therapeutic program. Low risk patients (Group 3, n=276) underwent no specific management. RESULTS: At the end of the survey and as a consequence of intensive management, lipid lowering therapy, antiplatelet drugs, and beta-blockers were more often prescribed in Group 2 than in Group 1 (55, 31 and 17% versus 36, 23, and 8% respectively, p<0.01). Planned coronary angiography in case of severe ischemia on MPI and revascularization were more frequent in Group 2 (16.2 and 8.9%) than in Group 1 (8.0 and 2.8% - p<0.01). At 19-month follow-up (96.7% completed), major event rate in Group 2 was significantly lower than in Group 1 (3.9 versus 9.8%, p<0.01) and similar to that of Group 3 (2.2%, NS). CONCLUSION: Easy-to-perform risk stratification is able to select diabetic patients with good medium-term prognosis. In clinically selected higher risk patients, an intensive medical therapy combined with coronary angiography +/- revascularization in case of large ischemia on MPI is effective to improve prognosis.

Long-term additive prognostic value of thallium-201 myocardial perfusion imaging over clinical and exercise stress test in low to intermediate risk patients : study in 1137 patients with 6-year follow-up.

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 /=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.

Prognostic value of thallium-201 single-photon emission computed tomographic myocardial perfusion imaging according to extent of myocardial defect. Study in 1,926 patients with follow-up at 33 months.

OBJECTIVES: This study was designed to assess the prognostic value of thallium-201 single-photon emission computed tomographic (thallium SPECT) perfusion imaging in patients evaluated for stable angina pectoris and to examine the relation, if any, between the presence and extent of myocardial defect and future fatal or nonfatal cardiovascular events (revascularization, secondary myocardial infarction). BACKGROUND: Compared with planar scintigraphy, thallium SPECT enables better evaluation of the extent of myocardial perfusion defect. However, its prognostic value has not yet been studied in a large population of patients. METHODS: Between 1987 and 1989 we studied 3,193 patients. After exclusion of patients with unstable angina, myocardial infarction during the previous month or earlier revascularization, 1,926 patients were followed up for 33 +/- 10 (mean +/- SD) months after stress thallium SPECT imaging (performed after exercise in 1,121 patients or during dipyridamole infusion in 805 patients). Thallium SPECT imaging of the left ventricle was divided into six segments. RESULTS: After normal thallium SPECT imaging (715 patients), the annual total and cardiovascular mortality rates were, respectively, 0.42%/year and 0.10%/year and were significantly higher after abnormal thallium SPECT imaging (respectively, 2.1%, relative risk 5, p = 0.012; 1.5%, relative risk 15, p < 0.0001 [log-rank test]). There was a significant relation between the number of abnormal segments and cardiovascular mortality during follow-up (p < 0.02) or the occurrence of nonfatal events (p < 0.001). The extent of defect on the initial scan provided the best SPECT variable for long-term prognosis. Thallium SPECT imaging provided additive prognostic information compared with other clinical variables (gender, previous myocardial infarction) and exercise electrocardiogram. CONCLUSIONS: In patients with stable angina, normal thallium SPECT imaging indicates a low risk patient, and the extent of myocardial defect is an important prognostic predictive factor.

Assessment of myocardial viability in patients with previous myocardial infarction by using single-photon emission computed tomography with a new metabolic tracer: [123I]-16-iodo-3-methylhexadecanoic acid (MIHA). Comparison with the rest-reinjection thallium-201 technique.

OBJECTIVES: We compared the ability of rest single-photon emission computed tomography (SPECT) with [123I]-16-iodo-3-methylhexadecanoic acid (MIHA) and the thallium-201 (Tl-201) rest-reinjection technique to detect myocardial viability after infarction. BACKGROUND: After myocardial infarction, MIHA frequently shows increased uptake in the areas with exercise Tl-201 defects (mismatch), even in patients with an irreversible Tl-201 reinjection defect. Whether such increased uptake is indicative of ischemic but viable myocardium is not known. METHODS: We studied 38 patients who 1) underwent exercise SPECT Tl-201 with rest-reinjection and rest SPECT with MIHA before undergoing percutaneous transluminal coronary angioplasty (PTCA) of an infarct-related coronary artery, and 2) were found to have successful revascularization at follow-up angiography. The relation between SPECT results before PTCA and subsequent improvement in left ventricular wall motion was assessed. RESULTS: A mismatch was evident before PTCA in 51 of 76 infarct-related segments and correlated with subsequent improvement in wall motion (overall accuracy 71%), even for the 27 segments whose exercise defects remained irreversible after Tl-201 reinjection (overall accuracy 81%). The finding of a mismatch clearly enhanced the results provided by the finding of > or = 50% Tl-201 uptake as determined at redistribution (p < 0.05), but not as determined at reinjection, although there was a trend toward a better specificity for the findings of a mismatch. CONCLUSIONS: MIHA is an efficient marker of viability inside exercise-underperfused areas after infarction, even in patients with irreversible Tl-201 reinjection defects. Assessment by conventional SPECT of a mismatch between results obtained with a metabolic tracer (MIHA) and a flow tracer analyzed at exercise (Tl-201) as a marker of myocardial viability is a promising area of research.

Prediction of cardiovascular events in clinically selected high-risk NIDDM patients. Prognostic value of exercise stress test and thallium-201 single-photon emission computed tomography.

OBJECTIVE: We evaluated the prognostic value of an exercise stress test and thallium-201 scintigraphy for the prediction of cardiac events in selected high-risk NIDDM patients. RESEARCH DESIGN AND METHODS: NIDDM patients (n = 158, 105 men, aged 63 +/- 9 years) with two or more of the following criteria were prospectively included: age > or = 65 years, active smoking, hypertension > 160/95 mmHg, hypercholesterolemia (cholesterol > 5.70 mmol/l or LDL > 3.10 mmol/l), peripheral artery disease, abnormal rest electrocardiogram, or microalbuminuria (20-200 micrograms/min). An exercise-stress scintigraphy was performed in 77 patients able to exercise, while a dipyridamole scintigraphy was performed in 80 patients unable to exercise. Follow-up was 23 +/- 17 months. Major end points were cardiac deaths or nonfatal myocardial infarction. RESULTS: The annual event rate was 7.31% (deaths: 8, myocardial infarction: 14). Independent predictors of events were as follows: an age > 60 (P = 0.02), an abnormal rest electrocardiogram (P = 0.02), microalbuminuria (P = 0.001), the inability to exercise (P = 0.009), and the presence of more than two defects on scintigraphy (P = 0.001). A cardiac death occurred in 1.3% of patients able to exercise versus 8.8% of patients unable to exercise (odds ratio = 6.8, P = 0.001). Among patients unable to exercise, large perfusion defects corresponded to an annual mortality rate of 22.3%. Conversely, the negative predictive value of a normal scintigraphy for the occurrence of death was 97%. CONCLUSIONS: Inability to exercise and large perfusion defects on thallium-201 scan are major predictors of future death and myocardial infarction in high-risk NIDDM patients.

Myocardial uptake of metaiodobenzylguanidine in patients with left ventricular hypertrophy secondary to valvular aortic stenosis.

UNLABELLED: The time course of myocardial uptake of metaiodobenzylguanidine ([123I]MIBG) was studied in 26 patients: seven control subjects (Group 1) and 13 patients with left ventricular hypertrophy secondary to valvular aortic stenosis. Seven of these had received no treatment (Group 2) and six were receiving amiodarone or digoxin (Group 3); six heart transplant recipients were investigated for extra neuronal myocardial uptake of [123I]MIBG (Group 4). The index of myocardial [123I]MIBG uptake was lower in Groups 2 and 3 than in Group 1 (Group 2: 1.42 +/- 0.07, p < 0.001; Group 3: amiodarone, 1.30 +/- 0.10, p < 0.05; digoxin, 1.22 +/- 0.06, p < 0.01; Group I: 1.83 +/- 0.18) and lower in Group 3 than in Group 2. Patients of Group 4 showed a much lower mean index of myocardial [123I]MIBG uptake than the control group (1.07 +/- 0.08, p < 0.001). IN CONCLUSION: 1. Patients with left ventricular hypertrophy secondary to valvular aortic stenosis were found to have lower myocardial [123I]MIBG activity and rapid washout than the control subjects. 2. Amiodarone and digoxin partially inhibited myocardial [123I] MIBG uptake. 3. Extra neuronal myocardial uptake of [123I]MIBG in humans only accounts for 13% of the total cardiac activity.

Value of myocardial defect size measured by thallium-201 SPECT: results of a multicenter trial comparing heparin and a new fibrinolytic agent.

In a multicenter randomized double-blind trial comparing heparin and a new fibrinolytic agent, anisoylated plasminogen streptokinase activator complex (APSAC), 231 patients presenting with a less than 5 hr acute myocardial infarction underwent a contrast angiography (CA) before the end of the first week of admission, and radionuclide cardiac blood-pool imaging and a 201Tl single photon emission computed tomography (SPECT) study before the end of the third week. Left ventricular ejection fraction (LVEF) and a wall motion score (WM) were calculated from CA. LVEF was also obtained from cardiac blood-pool imaging, and defect size (DS) from 201Tl SPECT. Results demonstrated that all parameters were significantly improved in patients treated with APSAC versus heparin (contrast LVEF 53 +/- 13 vs. 47 +/- 14 p less than 0.01, WM 9.8 +/- 6.5 vs. 13.3 +/- 7.9 p less than 0.001, radionuclide LVEF 43 +/- 12 vs. 40 +/- 13 p less than 0.05, DS 14 +/- 12 vs. 18 +/- 14 p less than 0.05). When the patients were divided according to infarct site and infarct-related coronary artery patency, it was demonstrated with all four parameters that the beneficial effect of APSAC can be largely explained by the lower incidence of vessel obstruction in this group (37% vs. 77% in the heparin group, p less than 0.001). It is concluded that (a) when compared with heparin and in the conditions of the trial, APSAC significantly improves the cardiac function and decreases the DS and (b) DS measured by 201Tl SPECT is as valuable a quantitative parameter of therapeutic evaluation as are LVEF and WM.

Bis(dithiocarbamato) nitrido technetium-99m radiopharmaceuticals: a class of neutral myocardial imaging agents.

UNLABELLED: The synthesis and biodistribution in various animal models (rat, dog, pig and monkey) of 99mTc radiopharmaceuticals containing the Tc = N multiple bond are reported. METHODS: The 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. RESULTS: No 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. CONCLUSION: The 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.

Biodistribution, dosimetry, and safety of myocardial perfusion imaging agent 99mTcN-NOET in healthy volunteers.

UNLABELLED: 99mTcN-NOET (bis[N-ethoxy,N-ethyl]dithiocarbamato nitrido technetium (V)) has been proposed for myocardial perfusion imaging. Biodistribution, safety, and dosimetry were studied in 10 healthy volunteers (5 at rest and 5 during exercise). METHODS: Biodistribution was studied by acquiring dynamic images up to 60 min after injection and whole-body images up to 24 h after injection. The MIRDOSE3 analysis program was used for radiation dosimetry calculations. RESULTS: Safety parameters measured to 48 h after injection revealed no clinically significant changes. Cardiac uptake of 99mTcN-NOET was high (2.9%-3%), with biologic half-life of 210-257 min on average. Lung uptake of 99mTcN-NOET was higher (10%-20%) but, on average, biologic half-life was shorter (1-77 min). Clearance from the blood was rapid (5% by 5 min). Radiation dosimetry calculations indicated an effective absorbed dose of 5.11 x 10(-3) mSv/MBq at rest and 5.38 x 10(-3) mSv/MBq after exercise. CONCLUSION: 99mTcN-NOET exhibits high cardiac uptake and an estimated effective absorbed dose comparable with that of the other 99mTc-labeled compounds used in myocardial perfusion imaging.

Effect of glucose on the distribution of iodine-123-IHA-16 between esterification and oxidation in canine myocardium.

To evaluate the effect of glucose perfusion on the myocardial metabolism of [123I]-16-iodo-9-hexadecenoic acid (IHA), the latter was injected intravenously into six fasting dogs perfused with a solution lacking glucose (controls) and seven fasting dogs perfused with glucose and insulin. The distribution of myocardial 123I among iodides, free IHA, and esterified IHA was measured in myocardial biopsy specimens. The increase in esterification and decrease in oxidation of IHA due to glucose were quantified using a compartmental mathematical model of myocardial IHA metabolism. Subsequently, in six control and six glucose-perfused dogs, cardiac radioactivity was measured with a scintillation camera for 1 hr following i.v. injection of IHA. Four different methods were used to analyze the myocardial time-activity curves and to calculate the distribution of IHA between oxidation and esterification. Results comparable to those provided by analysis of biopsy specimens can be obtained by considering the curve to be the sum of an exponential and a constant, or by analyzing it with a compartmental mathematical model.

Thallium-201 rest-reinjection and iodine-123-MIHA imaging of myocardial infarction: analysis of defect reversibility.

UNLABELLED: Rest SPECT imaging with [123I]-16-iodo-3-methylhexadecanoic acid (MIHA) frequently shows an increased level of uptake in areas with irreversible defects on exercise 201TI SPECT. Such mismatch patterns between flow (201TI) and metabolic (MIHA) tracers might correspond to areas with ischemic but viable myocardium misidentified by 201TI imaging. METHODS: Eighty-three patients with myocardial infarction underwent exercise SPECT 201TI with rest-reinjection and rest SPECT with MIHA. Defect areas on the exercise images were reversible on MIHA but not on 201TI reinjection images that were determined visually. The presence and extent of these areas were quantified from normalized uptake values for both tracers. RESULTS: In areas with irreversible 201TI reinjection defects, MIHA detected exercise defect reversibility in 59% of patients. In areas with irreversible 201TI reinjection defects, the extent of visually determined defect reversibility on MIHA scans was related to the quantified extent of areas with 201TI uptake > or = 50% of normal; the correlation, however, was weak. In 86% of patients, areas with > or = 50% 201TI uptake were larger than those that were reversible on MIHA. CONCLUSION: After myocardial infarction, rest SPECT with MIHA often enables visual detection of increased uptake in areas with irreversible 201TI reinjection defects.

Myocardial kinetics of TcN-NOET: a neutral lipophilic complex tracer of regional myocardial blood flow.

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.

Myocardial perfusion imaging with technetium-99m-Tc NOET: comparison with thallium-201 and coronary angiography.

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.

Additive value of thallium single-photon emission computed tomography myocardial imaging for prediction of perioperative events in clinically selected high cardiac risk patients having abdominal aortic surgery.

The present study was designed to prospectively evaluate whether reinjection thallium-201 single-photon emission computed tomography (SPECT) has a significant additive predictive value for occurrence of perioperative cardiac events in clinically selected patients at high cardiac risk undergoing abdominal aortic surgery. Of a group of 517 consecutive patients referred, 134 had > or = 2 of the following clinical or electrocardiographic cardiac risk variables: age > 70 years; history of myocardial infarction, angina, or congestive heart failure; diabetes mellitus; hypertension with severe left ventricular hypertrophy; and Q waves or ischemic ST-segment abnormalities on electrocardiogram at rest. Operation was performed after thallium SPECT study. Twelve patients (9%) had major perioperative events (cardiac death or nonfatal myocardial infarction) and 18 patients had other cardiac events (unstable angina, congestive heart failure, or severe ventricular tachyarrhythmia). Variables correlated with the occurrence of major events were history of myocardial infarction (p < 0.05) and the presence (p < 0.001) and number of segments with thallium reversible defects (p < 0.001). In multivariate analysis, history of myocardial infarction (p < 0.05) and the number of segments with reversible thallium defects (p < 0.001) were independent predictors. When all the cardiac events were taken into consideration, all the previous variables, as well as Q waves and ischemic ST abnormalities on the electrocardiogram, showed significant predictive value in both univariate and multivariate analyses. Furthermore, thallium SPECT imaging has an additive predictive value for major cardiac events over clinical and electrocardiographic risk factors. When performed on clinically selected patients at high cardiac risk undergoing abdominal aortic surgery, thallium SPECT demonstrates significant prognostic value for cardiac events over that provided by clinical variables alone.