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R C Reba

Publications and source records attributed to R C Reba.

At least 55 records · Page 3Linked to original sources
PubMed1992

The in vitro dissociation kinetics of (R,R)-[125I]4IQNB is reflected in the in vivo washout of the radioligand from rat brain.

We have determined the kinetics of dissociation of (R)-3-Quinuclidinyl (R)-4-[125I]Iodobenzilate ((R,R)-[125I]4IQNB) from muscarinic acetylcholine receptor preparations from the cortex, hippocampus, caudate/putamen, thalamus, pons and colliculate bodies. The dissociation curves are well described by a biexponential function and are consistent with subtype selectivity favoring slow dissociation from the M1, M3, and M4 receptors with a 20-fold faster dissociation rate for the M2 receptor. Following intravenous injection, (R,R)-[125I]4IQNB binds to receptor in the rat brain in concentrations which reflect the receptor concentration present in a structure. We determined the extent of radioligand present at two times, 2 and 24 hrs, as an indication of the relative proportions of m-AChR which exhibits rapid vs. slow dissociation of (R,R)-[125I]4IQNB. A good correlation between in vitro and in vivo results suggests that the relative populations of receptor subtypes can be imaged using in vivo pharmacokinetics of (R,R)-[125I]4IQNB.

Animals↗
PubMed1992

Synthesis, characterization and biodistribution of a new hexadentate aminethiol ligand labeled with Tc-99m.

A new hexadentate aminethiol ligand (TACNS) derived from triazacyclononane was synthesized and characterized for the development of technetium radiopharmaceuticals. The ligand formed a neutral, lipophilic and stable complex with [99mTc]pertechnetate in the presence of tin(II)tartarate as a reducing agent. The biodistribution of [99mTc]TACNS indicates slight uptake in brain (0.23% ID/organ at 5 min) with a washout at 30 min to 0.14% ID/organ. A small uptake in heart (0.48% ID at 5 min) was also observed. The characterization of [99mTc]TACNS complex using single crystal x-ray analysis and mass spectroscopy has shown that an Sn-N3S3 complex was formed in which tin is oxidized from Sn(II) to Sn(IV). Pertechnetate was incorporated into the complex as counter anion. The nature of the species formed with Tc-99 and "no-carrier-added" [99mTc]pertechnetate is different as confirmed by ratio TLC. From these results, it is demonstrated that sometimes it may be difficult to predict the structure of new technetium radiopharmaceuticals, especially when stannous ion is used as a reducing agent. Moreover, the nature of the chemical species may not be the same at millimolar and at nanomolar levels.

Animals↗
PubMed1992

Use of ex vivo binding to measure the brain concentrations of putative radioligands.

The development of radioligands capable of imaging brain receptors depends on, amongst other factors, the ability of such compounds to penetrate the blood-brain barrier. We describe an ex vivo binding technique for measuring the brain concentration of peripherally administered unlabeled compounds. This technique can be used early in the development of putative radioligands. The pharmacokinetics of brain penetration of three muscarinic antagonists are described: QNB, BrQNB and the 2-thienyl derivative of BrQNB and were found to compare favorably to previous studies using [3H]QNB. These studies demonstrate the effectiveness of ex vivo binding in assessing the brain concentration of peripherally administered unlabeled compounds.

Animals↗
PubMed1992

Radiolabeled products in rat liver and serum after administration of antibody-amide-DTPA-indium-111.

Anti-human serum albumin antibody (Ab) was used as a model antibody. Ab was conjugated with DTPA using cyclic DTPA dianhydride reaction and radiolabeled with 111In. The labeled Ab was purified by affinity chromatography. Size exclusion HPLC of this product showed 62% of 111In bound to monomeric Ab and 38% of the activity bound to antibody oligomers with molecular weights ranging from 300,000 to 450,000. The labeled antibody preparation was injected into the tail vein of rats. The radioactive substances in serum and the supernatant from liver homogenates were analyzed for molecular weight and immunoreactivity. Size exclusion HPLC of the serum samples indicated that the monomeric and dimeric Abs disappeared from the serum at a similar rate over a 48 h period. In addition, a new radioactive substance with an estimated molecular weight of 35,000 appeared in the serum. The immunoreactive fraction of the circulating 111In substances decreased slowly, somewhat proportional to the appearance of the metabolite. On the other hand, the immunoreactivity of the 111In substances in the supernatant from the liver homogenate decreased rapidly and no appreciable immunoreactivity was observed after 48 h. The labeled antibody was catabolized very rapidly in the liver and the major activity in the supernatant was associated with a small molecular weight metabolite which had a HPLC retention time identical to that of DTPA-111In. The second metabolite had an estimated molecular weight of 35,000. No radioactivity was associated with transferrin.

Animals↗
PubMed1992

A comparison of FDG PET and IQNB SPECT in normal subjects and in patients with dementia.

Prior studies of patients with dementia have found similar qualitative patterns of cerebral glucose utilization with [18F]2-fluoro-2-deoxyglucose (FDG) PET and of putative muscarinic receptor activity with [123I]3-quinuclidinyl-4-iodobenzilate (IQNB). This raised doubts about whether receptor binding determines IQNB distribution and whether clinical information in IQNB scans is unique. To compare the methods directly, 4 normal volunteers and 7 patients with dementia underwent FDG PET and high-resolution IQNB SPECT scans. In normal subjects, relative regional activity from the paired scans was only weakly correlated (r = 0.29). Some regions (e.g., thalamus, frontal cortex) showed a clear disassociation of activity. In demented patients, IQNB scans tended to show larger defects than FDG scans, although one focal defect appeared only with PET. Results suggest that IQNB SPECT data are not primarily related to general physiological activity or regional cerebral blood flow and are not explained by attenuation or volume-averaging artifacts. Further studies should investigate whether IQNB scanning is a more sensitive in vivo measure of the extent of Alzheimer's disease than is FDG PET.

Adult↗
PubMed1992

Compensation for three-dimensional detector response, attenuation and scatter in SPECT grey matter imaging using an iterative reconstruction algorithm which incorporates a high-resolution anatomical image.

The use of SPECT to diagnose physiological alterations in disease states depends on the potential of SPECT to provide a quantitatively accurate reconstructed image. However, the reconstructed values depend upon the shape and size of the brain region as strongly as they depend upon true radioactivity concentration. We report here the results of applying an iterative reconstruction algorithm (IRA) to compensate for shape- and size-dependence, as well as for attenuation and scatter. The IRA is designed only for the reconstruction of images for which the true radioactivity in the white matter within the actual brain is negligible compared with the true radioactivity in the grey matter within the actual brain. The IRA incorporates an accurate three-dimensional model of detector response and utilizes an MRI image which defines the anatomical features of the brain being imaged by segmenting the grey, white and ventricular regions. It is the assumption of radioactivity localization exclusively in the grey matter which permits the efficient incorporation of the MRI image. The IRA was validated by simulation studies that utilized a slice through the basal ganglia in the realistic Hoffman three-dimensional mathematical brain model. FBP images deviate significantly from true radioactivity distribution, whereas IRA images are nearly identical to true radioactivity distribution, except for random fluctuations due to the presence of statistical noise. These results indicate that the application of the IRA will permit SPECT to distinguish deficits due to true physiological changes from apparent deficits due to imaging/reconstruction artifacts.

Algorithms↗
PubMed1991

Binding of radioiodinated SPECT ligands to transfected cell membranes expressing single muscarinic receptor subtypes.

The equilibrium dissociation constant and the kinetic rate constants were determined for the binding of (R)-[3H]3-quinuclidinyl benzilate ([3H]QNB) and [125I]3-quinuclidinyl-4-iodobenzilate ((R,R)- and (R,S)-[125I]IQNB) to transfected cell membranes expressing one single muscarinic acetylcholine receptor (mAChR) subtype. The association and dissociation kinetics for the m2 subtype were more rapid than for the m1 and m3 subtypes. The differential kinetic properties may be useful for the single photon emission computed tomographic (SPECT) evaluation of regional mAChR subtype alterations in disease states.

Animals↗
PubMed1991

In vivo dissociation kinetics of [3H]quinuclidinyl benzilate: relationship to muscarinic receptor concentration and in vitro kinetics.

The in vivo washout kinetics of [3H]quinuclidinyl benzilate ([3H]QNB) varies significantly in various structures in the rat brain. The slowest washout rates are from the hippocampus, corpus striatum, and cortex, intermediate rates are exhibited from the thalamus and colliculi, while the fastest washout rate is from the cerebellum. We have also demonstrated a difference in the in vitro dissociation rates (k-1) of [3H]QNB from various structures. The k-1 for the hippocampus, corpus striatum and cortex, is two-fold slower than that observed in the thalamus, colliculi, and cerebellum. The differences in the in vitro dissociation kinetics are not, however, sufficient to explain the differences in the in vivo washout kinetics. We have developed a theoretical formulation which describes conditions under which the washout kinetics are a function of the concentration of receptor in a structure. Furthermore, we present a graphical method in which a plot of the reciprocal of the observed washout rate constant, 1/k(obs), vs receptor concentration is linear. Analysis of the washout kinetics of [3H]QNB from various structures of the CNS of rat were well described by this theory when the differences in in vitro k-1 are included.

Animals↗
PubMed1991

The distribution of cerebral muscarinic acetylcholine receptors in vivo in patients with dementia. A controlled study with 123IQNB and single photon emission computed tomography.

A high-affinity muscarinic receptor antagonist, 123IQNB (3-quinuclidinyl-4-iodobenzilate labeled with iodine 123), was used with single photon emission computed tomography to image muscarinic acetylcholine receptors in 14 patients with dementia and in 11 healthy controls. High-resolution single photon emission computed tomographic scanning was performed 21 hours after the intravenous administration of approximately 5 mCi of IQNB. In normal subjects, the images of retained ligand showed a consistent regional pattern that correlated with postmortem studies of the relative distribution of muscarinic receptors in the normal human brain, having high radioactivity counts in the basal ganglia, occipital cortex, and insular cortex, low counts in the thalamus, and virtually no counts in the cerebellum. Eight of 12 patients with a clinical diagnosis of Alzheimer's disease had obvious focal cortical defects in either frontal or posterior temporal cortex. Both patients with a clinical diagnosis of Pick's disease had obvious frontal and anterior temporal defects. A region of interest statistical analysis of relative regional activity revealed a significant reduction bilaterally in the posterior temporal cortex of the patients with Alzheimer's disease compared with controls. This study demonstrates the practicability of acetylcholine receptor imaging with 123IQNB and single photon emission computed tomography. The data suggest that focal abnormalities in muscarinic binding in vivo may characterize some patients with Alzheimer's disease and Pick's disease, but further studies are needed to address questions about partial volume artifacts and receptor quantification.

Adult↗
PubMed1991

Muscarinic receptor subtype selectivity of novel heterocyclic QNB analogues.

In an effort at synthesizing centrally-active subtype-selective antimuscarinic agents, we derivatized QNB (quinuclidinyl benzilate), a potent muscarinic antagonist, by replacing one of the phenyl groups with less lipophilic heterocyclic moieties. The displacement of [3H]-N-methyl scopolamine binding by these novel compounds to membranes from cells expressing m1-m4 receptor subtypes was determined. Most of the novel 4-bromo-QNB analogues were potent and slightly selective for m1 receptors. The 2-thienyl derivative was the most potent, exhibiting a 2-fold greater potency than BrQNB at m1 receptors, and a 4-fold greater potency at m2 receptors. This compound was also considerably less lipophilic than BrQNB as determined from its retention time on C18 reverse phase HPLC. This compound may therefore be useful both for pharmacological studies and as a candidate for a radioiodinated SPECT imaging agent for ml muscarinic receptors in human brain.

Binding, Competitive↗
PubMed1991

Synthesis and muscarinic cholinergic receptor affinities of 3-quinuclidinyl alpha-(alkoxyalkyl)-alpha-aryl-alpha-hydroxyacetates.

Seven analogues of 3-quinuclidinyl benzilate (QNB) in which one phenyl ring was replaced by an alkoxyalkyl moiety were synthesized and their affinities for the muscarinic cholinergic receptor determined. An oxygen in the beta-position of the moiety was not well-tolerated. By contrast, an oxygen in the gamma-position did not change the affinity for the muscarinic receptor. However, when a bromine was placed on the remaining phenyl ring, the affinity was significantly reduced in striking contrast to results obtained on halogenation of QNB.

Animals↗
PubMed1991

Urinary fibrinopeptide A in evaluation of patients with suspected acute pulmonary embolism. A prospective pilot study.

This pilot study assessed the urinary fibrinopeptide A (uFPA) levels and the combination of uFPA test plus ventilation/perfusion (V/Q) scan in the diagnostic evaluation of acute pulmonary embolism (PE). One hundred consecutive patients were studied prospectively. Twenty-nine patients fulfilled diagnostic criteria defined in this study (seven with and 22 without PE). The uFPA concentration was significantly higher in patients with than without PE (41.1 +/- 2.6 vs 4.8 +/- 2.5 ng/mg of creatinine, p less than 0.0001). In all patients with PE, the uFPA levels were higher than threshold value derived by adding 2 standard deviations to the mean uFPA concentration of patients without PE. In patients without PE, the V/Q scan was negative in 16, the uFPA test was negative in 18, and at least one of the tests was negative in 21. These preliminary data suggest that a negative uFPA test may be helpful in excluding PE and that uFPA in combination with V/Q lung scans may correctly exclude PE in more patients than either test alone. Further studies in a large unselected population are needed to confirm these results.

Acute Disease↗
PubMed1991

Three-dimensional SPECT simulations of a complex three-dimensional mathematical brain model and measurements of the three-dimensional physical brain phantom.

We have developed a three-dimensional computer simulation of SPECT imaging. We have applied the simulation procedure to the realistic mathematical Hoffman three-dimensional brain model to generate the projection data (in the absence of attenuation, scatter, or noise) of both a parallel-hole and a multidetector SPECT system with point-focusing collimators. The simulated projection data were then reconstructed using standard software. The projection data resulting from the distribution of grey matter alone, or grey and white matter, were simulated. The results of these simulations indicate the existence of significant qualitative and quantitative artifacts in reconstructed human brain images. For example, the reconstructed values for grey matter along a cortical circumferential profile in a transverse slice through the basal ganglia varied by a factor of 2.40 (parallel-hole) and 2.99 (point-focusing), although the original grey matter values were identical in all cortical regions in the model. We have compared the simulated reconstructed images with those obtained by imaging the physical three-dimensional Hoffman brain phantom, which was constructed based upon the same set of data from which the mathematical three-dimensional Hoffman brain model was derived. Although the simulation did not include all of the degrading factors present in the physical imaging, the two images were in good agreement, indicating the applicability of the simulation to a realistic situation and the importance of the detector resolution effect.

Artifacts↗
PubMed1991

Three-dimensional simulations of multidetector point-focusing SPECT imaging.

We have applied an efficient algorithm for mathematically simulating the three-dimensional (3-D) response of a SPECT imaging system with a depth-dependent 3-D point spread function (3-DPSF). The input object whose reconstructed image is to be simulated is restricted to a binary map; more complex objects may be treated as linear combinations of binary maps. The 3-D convolution reduces to a sequence of additions of a 3-D line spread function (3-DLSF), appropriately translated, to the 3-D response. We have simulated the projection data from a multidetector SPECT system with point-focusing collimators. The simulated projection data were then reconstructed using the manufacturer's software. The objects simulated included simple geometrical solids such as spheres and cylinders, as well as the distribution of muscarinic cholinergic receptors in a realistic brain slice. The results of these simulations indicate the existence of significant qualitative and quantitative artifacts in reconstructed human brain images.

Algorithms↗
PubMed1990

Specific in vivo binding of [125I]-iodomelatonin to melatonin receptors in rat brain.

The in vivo distribution of [125I]-2-iodomelatonin in rat brain was determined at different time intervals after intraarterial injection. After one hour, radioactivity in brain areas devoid of melatonin receptors had washed out to very low concentrations, but significant retention occurred in the medial basal hypothalamus (mbh) which contained the median eminence and in the anterior pituitary gland (ap), areas known to contain high concentrations of melatonin receptors. Coinjection of unlabelled melatonin reduced radioactivity concentrations in the ap and mbh by 44% and 75% respectively at one hour, whereas radiotracer concentrations in other regions remained unchanged. These results indicate the potential for the in vivo study of melatonin receptor concentration changes in human brain in disease states by means of single photon emission computed tomography.

Animals↗