BMS-747158-02 exhibited high and sustained cardiac uptake that was proportional to blood flow, and it represents a new class of PET myocardial perfusion imaging agent.
Background-Heart failure has been associated with impaired cardiac sympathetic neuronal function. Cardiac imaging with radiolabeled agents that are substrates for the neuronal norepinephrine transporter (NET) has demonstrated the potential to identify individuals at risk of cardiac events. N- 18 F]fluoro-propoxy)-benzyl]-guanidine (LMI1195) is a newly developed 18 F-labeled NET substrate designed to allow cardiac neuronal imaging with the high sensitivity, resolution, and quantification afforded by positron emission tomography (PET). Methods and Results-LMI1195 was evaluated in comparison with norepinephrine (NE) in vitro and 123 I-metaiodobenzylguanidine (MIBG) in vivo. The affinity (K i ) of LMI1195 for NET was 5.16Ϯ2.83 mol/L, similar to that of NE (3.36Ϯ2.77 mol/L) in a cell membrane-binding assay. Similarly, LMI1195 uptake kinetics examined in a human neuroblastoma cell line had K m and V max values of 1.44Ϯ0.76 mol/L and 6.05Ϯ3.09 pmol/million cells per minute, comparable to NE (2.01Ϯ0.85 mol/L and 6.23Ϯ1.52 pmol/million cells per minute). In rats, LMI1195 heart uptake at 15 and 60 minutes after intravenous administration was 2.36Ϯ0.38% and 2.16Ϯ0.38% injected dose per gram of tissue (%ID/g), similar to 123 I-MIBG (2.14Ϯ0.30 and 2.19Ϯ0.27%ID/g). However, the heart to liver and lung uptake ratios were significantly higher for LMI1195 than for 123 I-MIBG. In rabbits, desipramine (1 mg/kg), a selective NET inhibitor, blocked LMI1195 heart uptake by 82%, which was more effective than 123 I-MIBG (53%), at 1 hour after dosing. Sympathetic denervation with 6-hydroxydopamine, a neurotoxin, resulted in a marked (79%) decrease in LMI1195 heart uptake. Cardiac PET imaging with LMI1195 in rats, rabbits, and nonhuman primates revealed clear myocardium with low radioactivity levels in the blood, lung, and liver. Imaging in rabbits pretreated with desipramine showed reduced heart radioactivity levels in a dose-dependent manner. Additionally, imaging in sympathetically denervated rabbits resulted in low cardiac image intensity with LMI1195 but normal perfusion images with flurpiridaz F 18, a PET myocardial perfusion imaging agent. In nonhuman primates pretreated with desipramine (0.5 mg/kg), imaging with LMI1195 showed a 66% decrease in myocardial uptake. In a rat model of heart failure, the LMI1195 cardiac uptake decreased as heart failure progressed. Conclusions-LMI1195 is a novel 18 F imaging agent retained in the heart through the NET and allowing evaluation of the cardiac sympathetic neuronal function by PET imaging. (Circ Cardiovasc Imaging. 2011;4:435-443.)
Cortical neuronal activity depends on a balance between excitatory and inhibitory influences. Culturing of neurons on multi-electrode arrays (MEAs) has provided insight into the development and maintenance of neuronal networks. Herein, we seeded MEAs with murine embryonic cortical/hippocampal neurons at different densities (<150 or >1000 cells mm(-2)) and monitored resultant spontaneous signaling. Sparsely seeded cultures displayed a large number of bipolar, rapid, high-amplitude individual signals with no apparent temporal regularity. By contrast, densely seeded cultures instead displayed clusters of signals at regular intervals. These patterns were observed even within thinner and thicker areas of the same culture. GABAergic neurons (25% of total neurons in our cultures) mediated the differential signal patterns observed above, since addition of the inhibitory antagonist bicuculline to dense cultures and hippocampal slice cultures induced the signal pattern characteristic of sparse cultures. Sparsely seeded cultures likely lacked sufficient inhibitory neurons to modulate excitatory activity. Differential seeding of MEAs can provide a unique model for analyses of perturbation in the interaction between excitatory and inhibitory function during aging and neuropathological conditions where dysregulation of GABAergic neurons is a significant component.
Neuronal networks established on micro-electrode arrays provide useful models for synaptic plasticity. Whether or not this represents a facet of learning is debated since ex vivo networks are deprived of organismal interaction with the environment. We compared developmental signaling of such networks with and without stimulation with a prerecorded synaptic signal from another mature culture as a model of sensory input. Unstimulated networks displayed a developmental increase in individual signals that eventually declined, yielding a pattern containing organized bursts of signaling. Minimal stimulation, to model the onset of sensory input hastened the onset of developmental signaling. However, the overall developmental pattern of stimulated networks, including the total number and type of signals as well as the length of this developmental period, was identical to that of unstimulated networks. One interpretation of these findings is that ongoing plasticity may be essential to establish an appropriate platform for learning once sensory input ensues.
A series of fluorinated pyridazinone derivatives with IC50 values ranging from 8 to 4000 nM for the mitochondrial complex 1 (MC1) have been prepared. Structure-activity relationship (SAR) assessment indicated preference of the fluorine label to be incorporated on an alkyl side chain rather than directly on the pyridazinone moiety. Tissue distribution studies of a series of analogues ([18F] 22-28) in Sprague-Dawley (SD) rats identified [18F]27 as the most promising radiotracer with high uptake in cardiac tissue (3.41%ID/g; 30 min post injection) in addition to favorable heart to nontarget organ distribution ratios. MicroPET images of SD rats and nonhuman primates after [18F]27 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference.
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