No abstract

Recent in vitro studies suggest that lactate, rather than glucose, may be the preferred fuel for neuronal metabolism. The authors examined the effect of lactate on global brain glucose uptake in euglycemic human subjects using 18 fluoro-deoxyglucose (FDG) positron emission tomography (PET). Eight healthy men, aged 40 to 54 years, underwent a 60-minute FDG-PET scan on two occasions in random order. On one occasion, 6.72% sodium lactate was infused at a rate of 50 micro mol. kg-1. min-1 for 20 minutes and then reduced to 30 micro mol. kg-1. min-1; 1.4% sodium bicarbonate was infused as a control on the other occasion. Plasma glucose levels were not different between the two groups (5.3 +/- 0.23 and 5.3 +/- 0.24 mmol/L, P = 0.55). Plasma lactate was significantly elevated by lactate infusion (4.08 +/- 0.35 vs. 0.63 +/- 0.22 mmol/L, P < 0.0005. The whole-brain rate of glucose uptake was significantly reduced by approximately 17% during lactate infusion (0.195 +/- 0.022 vs. 0.234 +/- 0.020 micro mol. g-1. min-1, P = 0.001). The authors conclude that, in vivo in humans, circulating lactate is used by the brain at euglycemia, with sparing of glucose.

A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermal growth factor receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells compared to our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare these compounds. They were prepared mostly by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developed to prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved a safer cyclization step. We show that attaching a large lipophilic group at the para position of the 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also show the importance of a basic dialkylamino group at the end of the Michael acceptor for activity, due to intramolecular catalysis of the Michael addition. This, along with improved water solubility, resulted in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. Binding studies of one compound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474 cells. Furthermore, it demonstrated excellent oral activity, especially in HER-2 overexpressing xenografts. Compound 25o (HKI-272) was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

The effect of basal insulin on global and regional brain glucose uptake and metabolism in humans was studied using 18-fluorodeoxyglucose and positron emission tomography (FDG-PET). Eight healthy male volunteers aged 49.3 +/- 5.1 years were studied twice in random order. On each occasion, they received an infusion of 0.1 mg. kg(-1). min(-1) somatostatin to suppress endogenous insulin production. In one study 0.3 mU. kg(-1). min(-1) insulin was infused to replace basal circulating insulin levels, and in the other study a saline infusion was used as control. We sought stimulatory effects of basal insulin on brain glucose metabolism particularly in regions with deficiencies in the blood-brain barrier and high density of insulin receptors. Insulin levels were 27.07 +/- 1.3 mU/l with insulin replacement and 3.51 +/- 0.4 mU/l without (P = 0.001). Mean global rate of brain glucose utilization was 0.215 +/- 0.030 mmol. kg(-1). min(-1) without insulin and 0.245 +/- 0.021 mmol. kg(-1). min(-1) with insulin (P = 0.008, an average difference of 15.3 +/- 12.5%). Regional analysis using statistical parametric mapping showed that the effect of basal insulin was significantly less in the cerebellum (Z = 5.53, corrected P = 0.031). We conclude that basal insulin has a role in regulating global brain glucose uptake in humans, mostly marked in cortical areas.

No abstract

BackgroundPositron emission tomography (PET) imaging has a wide applicability in oncology, cardiology and neurology. However, a major drawback when imaging very active regions such as the bladder is the spill-in effect, leading to inaccurate quantification and obscured visualisation of nearby lesions. Therefore, this study aims at investigating and correcting for the spill-in effect from high-activity regions to the surroundings as a function of activity in the hot region, lesion size and location, system resolution and application of post-filtering using a recently proposed background correction technique. This study involves analytical simulations for the digital XCAT2 phantom and validation acquiring NEMA phantom and patient data with the GE Signa PET/MR scanner. Reconstructions were done using the ordered subset expectation maximisation (OSEM) algorithm. Dedicated point-spread function (OSEM+PSF) and a recently proposed background correction (OSEM+PSF+BC) were incorporated into the reconstruction for spill-in correction. The standardised uptake values (SUV) were compared for all reconstruction algorithms.ResultsThe simulation study revealed that lesions within 15–20 mm from the hot region were predominantly affected by the spill-in effect, leading to an increased bias and impaired lesion visualisation within the region. For OSEM, lesion SUVmax converged to the true value at low bladder activity, but as activity increased, there was an overestimation as much as 19% for proximal lesions (distance around 15–20 mm from the bladder edge) and 2–4% for distant lesions (distance larger than 20 mm from the bladder edge). As bladder SUV increases, the % SUV change for proximal lesions is about 31% and 6% for SUVmax and SUVmean, respectively, showing that the spill-in effect is more evident for the SUVmax than the SUVmean. Also, the application of post-filtering resulted in up to 65% increment in the spill-in effect around the bladder edges. For proximal lesions, PSF has no major improvement over OSEM because of the spill-in effect, coupled with the blurring effect by post-filtering. Within two voxels around the bladder, the spill-in effect in OSEM is 42% (32%), while for OSEM+PSF, it is 31% (19%), with (and without) post-filtering, respectively. But with OSEM+PSF+BC, the spill-in contribution from the bladder was relatively low (below 5%, either with or without post-filtering). These results were further validated using the NEMA phantom and patient data for which OSEM+PSF+BC showed about 70–80% spill-in reduction around the bladder edges and increased contrast-to-noise ratio up to 36% compared to OSEM and OSEM+PSF reconstructions without post-filtering.ConclusionThe spill-in effect is dependent on the activity in the hot region, lesion size and location, as well as post-filtering; and this is more evident in SUVmax than SUVmean. However, the recently proposed background correction method facilitates stability in quantification and enhances the contrast in lesions with low uptake.Electronic supplementary materialThe onli...

A series of 59 alpha-aryl-alpha-thioether-alkyl, -alkanenitrile, and -alkanecarboxylic acid methyl ester tetrahydroisoquinoline and isoindoline derivatives (15a-48) were synthesized and evaluated as multidrug resistance (MDR) reversal agents. The compounds were tested on S1-B1-20 human colon carcinoma cells selected for resistance to bisantrene. Both the cytotoxicity of the reversal agents and their ability to resensitize the cells to bisantrene were determined. All but two of these compounds (15q, 40) were more effective MDR reversal agents in vitro than verapamil (VRP), a calcium channel antagonist which also has been shown to possess MDR modulating activity. Several showed good activity in this assay (IC50's < 0.5 microM), the most potent being isoindolines 44 (IC50 0.26 microM) and 46 (IC50 0.26 microM) and tetrahydroisoquinolines 47 (IC50 0.29 microM) and 15m (IC50 0.30 microM). A number of compounds were evaluated in vivo against vincristine (VCR)-resistant murine P388 leukemia, as well as against human epidermoid carcinoma KB/8.5 implanted sc in athymic mice. The reversal agents which consistently showed the highest activity, together with low toxicity, were alpha-aryl-alpha-thiotolylalkanenitrile tetrahydroisoquinoline derivatives with electron-rich alkoxy substituents on the aromatic rings. Of the tested compounds, the most effective reversal agents for both tumor lines were 15h (33% increased life span at 12.5 mg/kg, 0.2 mg/kg VCR versus VCR alone in the VCR-resistant P388 leukemia model and 59% relative tumor growth at 50 mg/kg, 8 mg/kg doxorubicin versus doxorubicin alone in the KB/8.5 model) and 39a (48% increased life span at 50 mg/kg, 0.2 mg/kg VCR versus VCR alone in the VCR-resistant P388 leukemia model and 46% relative tumor growth at 25 mg/kg, 8 mg/kg doxorubicin versus doxorubicin alone in the KB/8.5 model). The mechanism of action of these compounds is believed to involve blocking the drug efflux pump, P-glycoprotein.