[en] Two iodinated acetals of D-glucose, 4,6-(R)-O-(2'-iodoethylidene)-α, β-D-glucose and 4,6-(R)-O-(4'-iodobenzylidene)-α, β-D-glucose , were prepared and their potential as suitable SPECT radioligands for imaging of glucose transporters was studied. Both are analogs of acetal D-glucose derivatives, which are known to bind to the exofacial sites of the glucose transport protein (GluT). To assess whether iodinated acetals 1 and 2 interacted with the glucose transporter, they were tested in vitro in human erythrocytes (GluT1) and neonatal rat cardiomyocytes (GluT4). The results indicated that 1 and 2 had a very low affinity for the glucose transporter and probably accumulated in cells. Study of their tissue distribution was carried out in the mouse in vivo: Both compounds showed fast tissue clearance with preferential renal elimination. It is concluded that iodinated acetals of D-glucose 1 and 2 are not suitable for GluT targeting in vivo

[en] 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

[en] Two anomeric analogues of glucose labelled with 123 iodine in position 6, proposed as tracers of glucose transport in vivo, have been synthesized: α- and β-methyl-6-deoxy-6-iodo-D-glucopyranoside (αMDIG and βMDIG). 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 αMDIG and βMDIG 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 αMDIG and βMDIG had similar repartitions in the mouse: myocardial uptake averaged 7% of the injected dose/g of organ at 2 min postinjection and αMDIG 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. αMDIG uptake was lowered in the presence of glucose transport inhibitors in each experimental model. An interaction between βMDIG and glucose transporters was observed only in human erythrocytes in suspension. Only αMDIG interacts with the glucose transporter, and thus could be used to estimate glucose transport in vivo

[en] The aim of this study was to assess the biological behavior of new radiolabeled glucose analogues proposed as tracers of glucose uptake in vivo and iodinated in position 3, 4, or 6. Biological results obtained in vitro on adipocytes and erythrocytes and in vivo in mice were compared to those obtained with the gold-standard tracer of glucose uptake, 2-deoxy-D-glucose. None of these molecules had the same biological behavior than 2-deoxy-D-glucose. Therefore, these compounds cannot be considered as tracers of glucose uptake

[en] A major goal of nuclear oncology is the development of new radiolabelled tracers as proliferation markers. Intracellular calcium waves play a fundamental role in the course of the cell cycle. These waves occur in non-excitable tumour cells via store-operated calcium channels (SOCCs). Bis(N-ethoxy, N-ethyldithiocarbamato) nitrido technetium (V)-99m (^99mTcN-NOET) has been shown to interact with L-type voltage-operated calcium channels (VOCCs) in cultured cardiomyocytes. Considering the analogy between VOCCs and SOCCs, we sought to determine whether ^99mTcN-NOET also binds to activated SOCCs in tumour cells in order to clarify the potential value of this tracer as a proliferation marker. Uptake kinetics of ^99mTcN-NOET were measured in human leukaemic HL-60 cells over 60 min and the effect of several calcium channel modulators on 1-min tracer uptake was studied. The uptake kinetics of ^99mTcN-NOET were compared both with the variations of cytosolic free calcium concentration measured by indo-1/AM and with the variations in the SG₂M cellular proliferation index. All calcium channel inhibitors significantly decreased the cellular uptake of ^99mTcN-NOET whereas the activator thapsigargin induced a significant 10% increase. In parallel, SOCC activation by thapsigargin, as measured using the indo-1/AM probe, was inhibited by nicardipine. These results indicate that the uptake of ^99mTcN-NOET is related to the activation of SOCCs. Finally, a correlation was observed between the tracer uptake and variations in the proliferation index SG₂M. The uptake of ^99mTcN-NOET seems to be related to SOCC activation and to cell proliferation in HL-60 cells. These results indicate that ^99mTcN-NOET might be a marker of cell proliferation. (orig.)

[en] Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using ¹²⁵I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. (orig.)

[en] Insulin resistance, implying depressed cellular sensitivity to insulin, is a risk factor for type 2 diabetes and cardiovascular disease. This study is the first step towards the development of a technique of insulin resistance measurement in humans with a new tracer of glucose transport, [¹²³I]6-deoxy-6-iodo-D-glucose (6DIG). We investigated 6DIG kinetics in anaesthetised control rats and in three models of insulin-resistant rats: fructose fed, Zucker and ZDF. The study of myocardial 6DIG activity was performed under two conditions: first, 6DIG was injected under the baseline condition and then it was injected after a bolus injection of insulin. After each injection, radioactivity was measured over 45 min by external detection via NaI probes, in the heart and blood. A tri-compartment model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the heart. These coefficients were significantly increased with insulin in control rats and did not change significantly in insulin-resistant rats. The ratio of the coefficient obtained under insulin to that obtained under basal conditions gave an index of cardiac insulin resistance for each animal. The mean values of these ratios were significantly lower in insulin-resistant than in control rats: 1.16 ± 0.06 vs 2.28 ± 0.18 (p < 0.001) for the fructose-fed group, 0.92 ± 0.05 vs 1.62 ± 0.25 (p < 0.01) for the Zucker group and 1.34 ± 0.06 vs 2.01 ± 0.26 (p < 0.05) for the ZDF group. These results show that 6DIG could be a useful tracer to image cardiac insulin resistance. (orig.)

[en] The molecular imaging of tumour neoangiogenesis currently represents a major field of research for the diagnostic and treatment strategy of solid tumours. Endothelial cells from tumour neovessels overexpress the α_vβ₃ integrin, which selectively binds to Arg-Gly-Asp (RGD)-containing peptides. We evaluated the potential of the novel radiotracer ^99mTc-RAFT-RGD for the non-invasive molecular imaging of α_vβ₃ integrin expression in mice models of tumour development. ^99mTc-RAFT-RGD, ^99mTc-cRGD (specific control) and ^99mTc-RAFT-RAD (non-specific control) were injected intravenously to mice bearing B16F0 or TS/A-pc tumours. In vivo whole-body tomographic imaging and post-mortem biodistribution studies were performed 60 min following tracer injection. Adjacent tumour slices were used to compare the localisation of neovessels from immunostaining and the pattern of ^99mTc-RAFT-RGD uptake from autoradiographic ex vivo imaging. Biodistribution studies indicated that ^99mTc-RAFT-RGD tumour uptake was significantly higher than that of ^99mTc-RAFT-RAD in B16F0 (2.4±0.5 vs 1.0±0.1%ID/g, respectively) and in TS/A-pc tumours (2.7±0.8 vs 0.7±0.1%ID/g, respectively). Immunohistochemical and autoradiographic studies indicated that ^99mTc-RAFT-RGD intratumoural uptake preferentially occurred in angiogenic areas. Tomographic imaging allowed tumour visualisation following injection of ^99mTc-RAFT-RGD and ^99mTc-cRGD with similar tumour-to-contralateral muscle (T/CM) ratios in B16F0 and in TS/A-pc tumours whereas ^99mTc-RAFT-RAD T/CM ratios did not allow tumour imaging. In accordance with the higher level of α_vβ₃ integrin expression on TS/A-pc tumours than on B16F0 tumours as determined from western blot and immunoprecipitation analyses, the ^99mTc-RAFT-RGD T/CM ratio was significantly higher in TS/A-pc than in B16F0 tumours. ^99mTc-RAFT-RGD allowed the in vivo imaging of α_vβ₃ integrin tumour expression. (orig.)

No abstract available

[en] Coronary microvascular dysfunction (CMVD) plays a major role in the occurrence of cardiovascular events (CVE). We recently suggested the clinical potential of myocardial perfusion entropy (MPE) quantification from SPECT myocardial perfusion images (MPI) for the prognosis of CVE occurrence. We hypothesized that the quantification of MPE from SPECT MPI would allow the assessment of CMVD-related MPE variations in a preclinical model of type 2 diabetes (T2D) including treatment with the anti-diabetic incretin liraglutide (LIR). Optimal conditions for the preclinical quantification of MPE using ${}^{201}$Tl SPECT MPI were determined in rats with a T2D-like condition induced by a high-fat diet and streptozotocin injection (feasibility study, n = 43). Using such conditions, echocardiography and post-mortem LV capillary density evaluation were then used in order to assess the effect of LIR and the ability of MPE to assess CMVD (therapeutic study, n = 39). The feasibility study identified dobutamine stress and acute NO synthase and cyclooxygenase inhibition as optimal conditions for the quantification of MPE, with significant increases in MPE being observed in T2D animals (P < 0.01 vs controls). In the therapeutic study, T2D rats were hyperglycemic (5.5 ± 0.5 vs 1.1 ± 0.3 g/L for controls, P < 0.001) and had a significantly lower left ventricular ejection fraction (LVEF) (65 ± 4% vs 74 ± 9%, P < 0.01) and LV capillary density (2400 ± 300 vs 2800 ± 600 mm${}^{-<!--\; ???\; -->3}$, P < 0.05). LIR partially restored glycemia (3.9 ± 0.6 g/L, P < 0.05 vs controls and T2D), totally prevented LVEF impairment (72 ± 7%, P = NS vs CTL), with no significant effect on capillary density. MPE was significantly increased in T2D rats (7.6 ± 0.5 vs 7.1 ± 0.5, P < 0.05), with no significant improvement in T2D-LIR rats (7.4 ± 0.4, P = NS vs controls and T2D). MPE quantification allowed the preclinical noninvasive assessment of CMVD. Both MPE and capillary density quantification suggested that LIR did not improve T2D-induced CMVD. The relevance of MPE for CMVD assessment warrants further clinical investigation.