The use of functional magnetic resonance imaging (fMRI) techniques for evaluation of pharmacologic stimuli has great potential for understanding neurotransmitter dynamics for a number of brain disorders, such as drug abuse, schizophrenia, epilepsy, or neurodegeneration. Unfortunately, blood oxygenation level-dependent (BOLD) imaging at common fields strengths, such as 1.5 or 3 T, has very low sensitivity and contrast-to-noise ratios (CNRs). We demonstrate here the utility of using an intravascular superparamagnetic iron oxide contrast agent with a long plasma half-life for evaluation of hemodynamic changes related to dopaminergic stimuli using amphetamine or the cocaine analog 2-carbomethoxy-3-(4-fluorophenyl)tropane (CFT). We refer to this technique as increased relaxation with iron oxide nanoparticles (IRON). Results obtained here show that even at field strengths as high as 4.7 T, one can obtain increases in CNR by factors of 2-3 over BOLD imaging that lead to greater than an order of magnitude increase in statistical power with greatly increased sensitivity to hemodynamic changes in brain regions difficult to observe using BOLD imaging. Furthermore, use of the intravascular contrast agent allows for a meaningful physiologic parameter to be measured (relative cerebral blood volume (rCBV)), compared to conventional BOLD imaging. J. Magn. THE TECHNIQUE OF FUNCTIONAL MAGNETIC resonance imaging (fMRI) using either relative cerebral blood volume (rCBV) (1), blood oxygenation level-dependent (BOLD) (2,3), or T1-based cerebral blood flow (CBF) techniques (3,4) has led to a revolution in brain mapping. By far the most common application is the BOLD technique. Unfortunately, contrast-to-noise ratios (CNRs) of BOLD are low, especially at field strengths such as 1.5 T (5). In addition, BOLD contrast has no simple relationship to any unique physiologic parameter, although with appropriate calibration and modeling in ideal circumstances, it can be used to infer regional oxygen consumption (6,7). CNRs for flow-based MR measurements based upon T1 changes (3,4,8) are generally even lower than they are for BOLD.Conventional BOLD imaging is often sensitivity limited at field strengths such as 1.5 T. For example, percent signal changes in occipital cortex with photic stimulation protocols are on the order of 2%-3% with a standard gradient echo (GE) EPI acquisition (long TR, moderate TE (30 -50 msec)). Other stimuli of interest, particularly those associated with cognitive tasks, are most often smaller in magnitude and require intersubject averaging. This is obviously inappropriate for clinical studies where one might need data from individual patients. Use of BOLD for mapping of neuronal activation after a pharmacologic challenge has an even greater number of limitations than mapping task activation in conventional fMRI. Generally, pharmacologic stimuli have a longer and uncontrolled time duration, compared to task activation in fMRI (9). Due to the long time course of the pharmacodynamic changes that may take place, BOLD sig...
Purpose:To evaluate the diagnostic and prognostic potential of a new protein-binding contrast medium, B22956/1, for quantitatively characterizing tumor microvessels by MRI and monitoring response to antiangiogenic therapy. Materials and Methods:Dynamic contrast-enhanced MRI (DCE-MRI) was performed in an experimental cancer model with the use of the novel protein-binding agent B22956/1, a low molecular contrast agent (ProHance™), and a macromolecular contrast medium, albumin-(Gd-DTPA). MDA-MB-435, a human cancer cell line, was implanted in 22 athymic rats. Animals were assigned randomly to a control (saline) or drug-treated (Avastin™) group. MRI was performed at baseline and after nine days of treatment. The transendothelial permeability (K PS ) and the fractional blood volume (fBV) were estimated from the kinetic analysis of dynamic MR data using a two-compartment model. Tumor growth was also measured from volumetric MRI.Results: Tumors grew more slowly, although not significantly (P ϭ 0.07), in the drug-treated group. The K PS determined for B22956/1 decreased significantly in the drugtreated group compared to baseline (P Ͻ 0.05), and progressed significantly in the control group. However, no significant changes were resolved with the use of ProHance or albumin-(Gd-DTPA). Conclusion:With the use of appropriate contrast media, the therapeutic effects of an anti-VEGF antibody on tumor microvessels can be monitored by dynamic MRI. The dynamic range of permeability to B22956/1, and the sensitivity to change of this parameter suggest a potential application in the clinical setting.
I The pharmacokinetic behaviour of the psychotropic drug clobazam, a 1,5 benzodiazepine, and its metabolism were studied with the "4C-labelled compound in rats, dogs, monkeys and man. The absorption was practically complete in all three animal species. Clobazam was not excreted in the unchanged form by all species. The main metabolite in plasma of monkeys, dogs and man was N-demethylclobazam. The metabolites were partially in the conjugated form.2 The binding to serum proteins (concentration range 0.05-10 jg/ml serum) amounted to between 66% (in rats) and 85% (in man). The maximal levels of total radioactivity (original compound and metabolites) in blood were 0.24 + 0.043 ig Equ/ml (2-4 h) in doses and 0.67-0.82 jg Equ/ml (0.5-1 h) in rhesus monkeys. These levels were markedly higher than those in rats with values of 0.064 + 0.012 jig Equ/ml (-0.5 h). The elimination of radioactivity from blood occurred in two phases.3 After repeated daily administration of oral doses, the 24-h blood levels accumulated in rats to about three times the initial value. In dogs the 24-h serum concentrations remained practically unchanged. Long-term treatment with clobazam in monkeys neither caused enzyme induction nor other processes retarding metabolism and elimination. 4 Both after a single oral and intravenous dose, more than two-thirds of the radioactivity administered to rats was excreted with the faeces. Dogs, however, excreted about three-quarters of the radioactivity with the urine, irrespective of the route of administration. In monkeys, the excretion also occurred mainly in the urine. In all three species, renal excretion was similarly rapid to that from blood or plasma. 5 Apart from gastro-intestinal tract, liver and kidneys, the distribution in rats and dogs was remarkably even within the range of maximal blood levels. In the rat brain, the concentration amounted to only one-third of that in the blood. Special accumulations were not found. In dogs, the concentration in the brain was as high as that in the blood. 6 In rats, kinetics and metabolism were not significantly changed by pregnancy. 7 For metabolism studies in the four species (man, monkey, dog and rat) urine and faeces (and in some cases also serum) were examined after a single dose or repeated administration. The number and kind of metabolites detected in the individual species were partially different. In autoradiographic studies, exceptionally up to 14 radioactive spots were found for clobazam. 8 The structures of the metabolites were elucidated by independent methods, mainly mass spectrometry. In addition to the original substance, eight metabolites were identified for clobazam amounting to 70-90%/o of the total number of metabolites, depending on the species.The two most important chemical changes of clobazam during metabolism are dealkylation and hydroxylation. Dealkylation at nitrogen-(I), particularly pronounced in the species dog, does not differ between the 1,4-and 1,5-benzodiazepines. The difference in metabolism is only pronounced in oxidative deco...
Receptor supersensitivity is an important concept for understanding neurotransmitter and receptor dynamics. Traditionally, detection of receptor supersensitivity has been performed using autoradiography or positron emission tomography (PET). We show that use of magnetic resonance imaging (MRI) not only enables one to detect dopaminergic supersensitivity, but that the hemodynamic time course reflective of this fact is different in different brain regions. In rats unilaterally lesioned with intranigral 6-hydroxydopamine, apomorphine injections lead to a large increase in hemodynamic response (cerebral blood volume, CBV) in the striato-thalamo-cortico circuit on the lesioned side but had little effect on the intact side. Amphetamine injections lead to increases in hemodynamic responses on the intact side and little on the lesioned side in the same animals. The time course for the increase in CBV after either amphetamine or apomorphine administration was longer in striatum and thalamus than in frontal cortex. (11)C-PET studies of ligands which bind to the dopamine transporter (2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1, 5-naphthalnendisulfonate, WIN 35, 428 or CFT) and D2 receptors (raclopride) confirm that there is a loss of presynaptic dopamine terminals as well as upregulation of D2 receptors in striatum in these same animals. Pharmacologic MRI should become a sensitive tool to measure functional supersensitivity in humans, providing a complementary picture to that generated using PET studies of direct receptor binding.
Weak protein binding can substantially increase the efficacy of gadolinium chelates as general purpose contrast agents for MRI.
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