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R C Reba

Publications and source records attributed to R C Reba.

At least 37 records · Page 2Linked to original sources
PubMed1995

Tumor receptor imaging: proceedings of the National Cancer Institute workshop, review of current work, and prospective for further investigations.

In February 1994, the National Cancer Institute held a workshop to evaluate the current and future role of emission tomographic imaging methods, positron emission tomography and single-photon emission computed tomography, in improving the accuracy of cancer diagnosis and the effectiveness of treatment and in elucidating basic aspects of human cancer biology. Reviews covered many of the receptor and transport systems for hormones and growth factors, as well as metabolic changes important in human cancer, and topical presentations reviewed the current status of receptor-based imaging in the most well-characterized systems: somatostatin receptor imaging of neuroendocrine tumors, estrogen receptor imaging of breast cancer, and epidermal growth factor receptor and tumor metabolic imaging. A critical analysis was made of the current research and of new directions for the future development and use of receptor-imaging methods in oncology. In each area, recommendations were made for further investigation, where emerging understanding of tumor cell biology and defined molecular targets might be combined with the methods of radiopharmaceutical design and evaluation, to develop new approaches to critical issues in the diagnosis, staging, and treatment of cancer through tumor receptor imaging.

Humans↗
PubMed1994

3-alpha-Chlorimperialine: an M2-selective muscarinic receptor antagonist that penetrates into brain.

Muscarinic M2 receptors have been found to be severely depleted in post-mortem brains of Alzheimer's patients. This loss of receptor may represent a useful diagnostic marker, if it could be quantitatively imaged with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. In order to develop a radioligand with selectivity for muscarinic M2 receptors, we now report that 3-alpha-chlorimperialine is a potent M2 receptor antagonist with a Ki of 0.32 nM at M2 receptors, a 12-fold selectivity for M2 over M1 receptors, and a 5-fold selectivity for M2 over M4 receptors. Furthermore, 2% of the injected dose of 3-alpha-chlorimperialine per gram tissue penetrates into brain within 30 min, then washes out gradually. Taken together, these studies demonstrate that 3-alpha-chlorimperialine is a potent M2-selective muscarinic antagonist that penetrates into brain and may be a useful substrate for radioiodination and subsequent imaging of brain muscarinic M2 receptors.

Animals↗
PubMed1994

[3H]QNB displays in vivo selectivity for the m2 subtype.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. [3H](R)-3-quinuclidinylbenzilate ([3H]QNB) is commonly used for performing in vitro studies of the muscarinic acetylcholine receptor (mAChR), either with membrane homogenates or with autoradiographic slices, in which [3H]QNB is nonsubtype-selective. We report here the results of in vivo studies, using both carrier-free and low specific activity [3H]QNB, which show that [3H]QNB exhibits a substantial in vivo m2-selectivity. Previously reported in vivo (R)-3-quinuclidinyl (R)-4-iodobenzilate ((R,R)-[125I]IQNB) binding appears to be nonsubtype-selective. Apparently the bulky iodine substitution in the 4 position reduces the subtype selectivity of QNB. It is possible that a less bulky fluorine substitution might permit retention of the selectivity exhibited by QNB itself. We conclude that a suitably radiolabeled derivative of QNB, possibly labeled with 18F, may be of potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD.

Animals↗
PubMed1994

Muscarinic receptor selectivities of 3-Quinuclidinyl 8-xanthenecarboxylate (QNX) in rat brain.

We have determined the binding of (R)-3-Quinuclidinyl 8-xanthenecarboxylate to muscarinic acetylcholine receptor preparations from rat cortex, hippocampus, caudate/putamen, thalamus, pons and colliculate bodies. The competition curves determined with [3H]quinuclidinyl benzilate as the radioligand are well described by a two site model with a difference in affinity between the two sites of 12-fold. The proportions of high affinity site vary from 100% in the caudate/putamen to 0% in the pons/medulla. The selectivities are different from those measured by pirenzepine and are consistent with QNX exhibiting similar affinity for the M1, M3, and M4 receptors with lower affinity for the M2 receptor. This assignment was confirmed by determining the affinities of QNX for the cloned receptor subtypes.

Animals↗
PubMed1994

Kinetic analysis of rat exocrine gland muscarinic receptors in vivo.

Recently we employed two enantiomers of the muscarinic antagonist quinuclidinyl iodobenzilate (IQNB), and pharmacokinetic analyses, to define and quantitate nonspecific and specific binding to rat parotid gland muscarinic acetylcholine receptors (mAChRs) in vivo (Hiramatsu et al., 1993). The present studies were designed to utilize this same approach for evaluating mAChRs in three other morphologically different rat exocrine glands: the submandibular, sublingual and lacrimal glands. The metabolism and tissue distribution of the intravenously injected IQNB enantiomers were determined, and the resulting data were assessed in terms of their goodness of fit to several multicompartmental models. All three exocrine glands showed substantial nonspecific ligand distribution as measured with the receptor-inert enantiomer (SS)-IQNB. Nonspecific distribution represented 45, 21 and 36% of total ligand distribution in submandibular, sublingual and lacrimal glands, respectively, as measured with the receptor-active enantiomer (RR)-IQNB. The rank order of the binding potential, kinetically equivalent to Bmax/Kd, for (RR)-IQNB and these mAChRs was lacrimal > sublingual > submandibular glands (674 +/- 235 > 575 +/- 109 > 345 +/- 29). These results demonstrate that specific mAChRs in the exocrine glands can be measured in vivo with the (RR)-IQNB enantiomer and that despite some small quantitative differences, the distribution of (RR)- and (SS)-IQNB is similar in the three exocrine glands but is substantially different from that in brain and heart.

Animals↗
PubMed1993

Synthesis and structure-activity relationship of some 5-[[[(dialkylamino)alkyl]-1-piperidinyl]acetyl]-10,11-dihydro-5H- benzo[b,e][1,4]diazepin-11-ones as M2-selective antimuscarinics.

A series of 5-[[[(dialkylamino)alkyl]-1-piperidinyl]acetyl]- 10,11-dihydro-5H-dibenzo[b,e][1,4]-diazepin-11-ones were prepared as potential M2-selective ligands. The compounds were evaluated for their affinity and selectivity for the muscarinic cholinergic receptor. The best M2-selective antimuscarinic agent studied is 5-[[4-[4-diethylamino)butyl]-1- piperidinyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11- one, which is approximately 10 times more potent at M2 receptors than previously known compounds such as 11-[[4-[4-(diethylamino)butyl]- 1-piperidinyl]acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one (AQ-RA 741).

Animals↗
PubMed1993

A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. In our efforts to prepare such a radioligand, we have used competition studies against currently existing muscarinic receptor radioligands to infer the in vitro and in vivo properties of a novel muscarinic receptor ligand, 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H - -dibenzo [b,e][1,4]diazepin-11-one (DIBD). In vitro competition studies against [3H](R)-3-quinuclidinylbenzilate ([3H]QNB) and [3H]N-methylscopolamine ([3H]NMS), using membranes derived from transfected cells expressing only m1, m2, m3, or m4 receptor subtypes, indicate that DIBD is selective for m2/m4 over m1/m3. In vivo competition studies against (R,R)-[125I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[125I]IQNB versus the percentage of each of the receptor subtypes indicates that DIBD competes more effectively in those brain regions which are known to be enriched in the m2, relative to the m1, m3, and m4, receptor subtype; however, analysis of the data using a mathematical model shows that caution is required when interpreting the in vivo results. We conclude that a suitably radiolabeled derivative of DIBD may be of potential use in emission tomographic study of changes in m2 receptors in the central nervous system.

Animals↗
PubMed1993

An improved synthesis of [125I]N-(diethylaminoethyl)-4-iodobenzamide: a potential ligand for imaging malignant melanoma.

To improve the radiolabeling yield and the specific activity of [125I]N-(2-diethylaminoethyl)-4-iodobenzamide (DAB), the aryltributyltin precursor was synthesized from the N-(2-diethylaminoethyl)-4-bromobenzamide derivative by palladium catalyzed stannylation using bis(tributyltin). The radiolabeled product, [125I]DAB, was obtained by an iododestannylation reaction in high radiochemical yields (85-94%, radiochemical purity, > 98%) using chloramine-T as an oxidizing agent. The specific activity was greater than 1600 Ci/mmol. The biodistribution studies in nude mice implanted with human malignant melanoma xenograft showed a good tumor uptake (6.14% ID/g at 1 h, 2.81% ID/g at 6 h and 0.42% ID/g at 24 h) of [125I]DAB. Unfortunately, a high uptake in the non-target organs, such as liver and lung, was found. At 1 h post-injection the activity level in liver and lung was 11.76 and 7.58% ID/g, respectively. A slow clearance of activity from liver and lung was observed at 6 h (3.43 and 0.49% ID/g). These results demonstrate that iodinated IDAB is a potential radiopharmaceutical for the management of patients with malignant melanoma.

Animals↗
PubMed1993

Kinetic analysis of rat parotid gland muscarinic receptors in vivo: comparison with brain and heart.

(RR)- and (SS)-quinuclidinyl iodobenzilate enantiomers [(RR)- and (SS)-IQNB, active and inert, respectively] have been synthesized for quantitative evaluation of muscarinic acetylcholine receptor (mAChR) binding. Pharmacokinetic approaches have not been used previously to assess in vivo IQNB binding in nonexcitable tissues. We have applied this method to examine mAChRs in rat parotid gland in comparison to those in brain and heart. Short-term infusion studies in vivo showed that the "instantaneous" reversible binding of (RR)- and (SS)-IQNB was high in the parotid (greater nonspecific binding potential), intermediate in the heart, and lowest in cortex and cerebellum. Long-term bolus injection experiments showed that the parotid gland mAChRs possessed a binding potential for receptor specific sites (380), which was intermediate between that of parietal cortex (930) and cerebellum (10) and greater than that of heart (165). In vitro binding to plasma membranes was generally consistent with the in vivo findings. In aggregate, these studies show that mAChRs can be evaluated in vivo in a nonexcitable tissue with the use of stereospecific ligands and a pharmacokinetic approach. The data suggest that IQNB, a mAChR antagonist, can identify characteristics of specific binding sites, which may reflect tissue differences.

Animals↗
PubMed1993

A malignant melanoma imaging agent: synthesis, characterization, in vitro binding and biodistribution of iodine-125-(2-piperidinylaminoethyl)4-iodobenzamide.

In order to develop improved radiopharmaceuticals for imaging malignant melanoma, we have synthesized and characterized 125I-and 131I-labeled (2-piperidinylaminoethyl)4-iodobenzamide (PAB). In vitro binding profiles of IPAB and N-(2-diethylaminoethyl)4-iodobenzamide (IDAB, a structurally related analog of IPAB) for a variety of neurotransmitter receptors suggested that both IPAB and IDAB possessed a high sigma-1 affinity and a low affinity for sigma-2 sites. In vitro homologous competition binding studies of [125I]PAB with human malignant melanoma cell A2058 showed that the tracer was bound to the cells with a high affinity (Ki = 6.0 nM) and that the binding was saturable. Biodistribution studies in nude mice implanted with human malignant melanoma xenografts showed good tumor uptake (3.87% ID/g at 1 hr, 2.91% ID/g at 6 hr and 1.02% ID/g at 24 hr) of [125I]PAB. High tumor-to-nontarget organ ratios were obtained at 24 hr postinjection. Tumor-to-blood, liver, muscle, lung, intestines, heart and brain ratios at 24 hr were 17.80, 3.88, 94.58, 14.29, 10.87, 37.07 and 90.01, respectively. Tumor imaging with [131I]PAB in a nude mice model xenografted with human malignant melanoma at 24 hr clearly delineated the tumor with very little activity in any other organ. These results demonstrate that sigma-1 receptors could be used as external markers for malignant melanoma.

Animals↗
PubMed1993

PET and SPECT: opportunities and challenges for psychiatry.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are the most advanced technologies available for the functional imaging of the brain, surpassing magnetic resonance imaging (MRI) and computed tomography (CT) scanners in potential clinical and research applications in neuropsychiatry. PET deals with a small number of radionuclides with short physical half-lives and an exclusive energy of 511 keV; SPECT utilizes an ensemble of radionuclides that exhibit moderate physical half-lives, each with its own characteristic spectrum of energy. PET imaging instrumentation requires substantial refinements to enable utilization with high-energy photons, larger data sets, and a high magnitude of information flow per unit of time. The instrumentation enables greater sensitivity and resolution, as compared with SPECT, but requires a more extensive data acquisition and processing infrastructure, resulting in a significantly higher system cost. SPECT has a number of price/performance alternatives in configuring a system, and has further cost advantages in that it utilizes widely available chemical tracers.

Brain↗
PubMed1993

Evaluation of reconstruction algorithms in SPECT neuroimaging: I. Comparison of statistical noise in SPECT neuroimages with 'naive' and 'realistic' predictions.

In the presence of statistical noise, an iterative reconstruction algorithm (IRA) for the quantitative reconstruction of single-photon-emission computed tomographic (SPECT) brain images overcomes major limitations of applying the standard filtered back projection (FBP) reconstruction algorithm to projection data which have been degraded by convolution of the true radioactivity distribution with a finite-resolution distance-dependent detector response: (a) the non-uniformity within the grey (or white) matter voxels which results even though the true model is uniform within these voxels; (b) a significantly lower ratio of grey/white matter voxel values than in the true model; and (c) an inability to detect an altered radioactivity value within the grey (or white) matter voxels. It is normally expected that an algorithm which improves spatial resolution and quantitative accuracy might also increase the magnitude of the statistical noise in the reconstructed image. However, the noise properties in the IRA images are very similar to those in the FBP images. In fact, the noise magnitude in both the FBP and IRA images is only slightly greater than that computed by the 'naive prediction', which presumably is a lower limit to the amount of statistical noise in a reconstructed image. Thus, the IRA should provide the potential for quantitative SPECT imaging of normal physiological responses or diseases involving both the brain grey and white matter.

Algorithms↗
PubMed1993

Evaluation of reconstruction algorithms in SPECT neuroimaging: II. Computation of deterministic and statistical error components.

For the reconstruction of a series of computer simulations of statistically-independent noisy realizations of projection data, the total error of the ith reconstructed voxel in the rth realization, Er,i, is composed of the statistical error, Sr,i, and the (deterministic) inaccuracy in the presence of noise, Di+. Di+ is composed of the (deterministic) inaccuracy in the absence of noise, Di-, and the (deterministic) additional inaccuracy in the presence of noise, Di delta. E(Er,i), the theoretical expected value of Er,i, is given by E(Er,i) = E(Di+) + E(Sr,i). Similarly, E(Di+) = E(Di-) + E(Di delta). The corresponding theoretical variances are given by sigma 2(Er,i) = sigma 2(Di+)+2C(Di+, Sr,i)+ sigma 2(Sr,i) and sigma 2(Di+) = sigma 2(Di-)+2C(Di-, Di delta)+ sigma 2(Di delta), where C(.,.) is the covariance. We have utilized these relationships to evaluate three reconstruction algorithms: standard filtered back projection (FBP), an iterative reconstruction algorithm (IRA), and a version of the IRA which incorporates a linear transformation (TIRA). For simulated brain images in which the projection data (500,000 events detected) were degraded as the result of convolution of the true radioactivity distribution with a realistic distance-dependent detector response function, for FBP the major contribution to both E(Er,i) and sigma 2(Er,i) was Di-. For the IRA and TIRA, the major contributions to E(Er,i) were Di- and Di delta, and the major contribution to sigma 2(Er,i) was Sr,i, although in some cases Di delta was also a contributing factor. Furthermore, the errors due to sigma 2(Er,i) (that is, [sigma 2(Er,i)]0.5) were more severe than those due to E(Er,i). We conclude that, in contrast to FBP, the effects of statistical noise are an important limiting factor for the IRA and TIRA, and that the future development of tomographic devices with higher sensitivity would expand the quantitative potential of the IRA and TIRA.

Algorithms↗
PubMed1992

A novel m2-selective muscarinic antagonist: binding characteristics and autoradiographic distribution in rat brain.

Although several m2-selective muscarinic antagonists have been described, they are not particularly potent. Thus, the development of potent m2-selective compounds remains an important goal. We now report that a bio-isoster of AQ-RA 741 is both one order of magnitude more potent and slightly more selective than previously described compounds. DIBA, a di-benzo derivative of AQ-RA 741, in which the pyridine of the tricycle is replaced with a benzene ring, had Ki values of 4, 0.3, 11 and 2 nM at m1 through m4 receptors, respectively. These values were determined in competition studies with [3H]N-methylscopolamine ([3H]NMS) in membranes from transfected A9 L cells (m1 and m3), rat heart (m2) and NG108-15 cells (m4). AQ-RA 741 had Ki values of 34, 4, 86 and 15 nM at each of these receptors. The autoradiographic distribution of DIBA binding sites was determined by competition studies of [3H]NMS in rat brain. At low concentration, DIBA reduced [3H]NMS binding most significantly from superior colliculi, thalamus, hypothalamus, pontine nucleus, and interpeduncular nucleus, and not appreciably from caudate nucleus, cerebral cortical regions, or hippocampus, consistent with its binding to m2 receptors. These data indicate that DIBA is the most potent, m2-selective muscarinic antagonist yet described. DIBA should therefore become a useful probe in future studies of muscarinic function.

Animals↗
PubMed1992

Synthesis and receptor affinities of new 3-quinuclidinyl alpha-heteroaryl-alpha-aryl-alpha-hydroxyacetates.

Five analogues of 3-quinuclidinyl benzilate were prepared in which one phenyl ring was substituted by a heterocycle; a bromine was included on either the remaining phenyl or the heterocycle to provide information relating to the affinity of potential radiohalogenated derivatives. Their affinities for the muscarinic cholinergic receptor were determined. Replacing a phenyl ring with either the 2- or 3-furyl moiety or the 2- or 3-thienyl moiety did not significantly alter the affinity to the muscarinic receptor compared with 3-quinuclidinyl 4-bromobenzilate.

Animals↗
PubMed1992

Pharmacokinetic simulations of SPECT quantitation of the M2 muscarinic neuroreceptor subtype in disease states using radioiodinated (R,R)-4IQNB.

Alzheimer's disease (AD) involves selective loss of muscarinic M2, but not M1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of M2 receptors in AD is limited by the fact that there is currently no available M2-selective radioligand which can penetrate the blood-brain barrier. However, by taking advantage of the different pharmacokinetic properties of (R,R)-[123I]IQNB for the M1 and M2 subtypes, it may be possible to estimate losses in M2. It has previously been hypothesized that the difference between an early study and a late study should provide information on the M2 receptor population. In order to test this hypothesis, we present here the results of pharmacokinetic simulations of the in vivo localization of (R,R)-[123I]IQNB in brain regions containing various proportions of M1 and M2 subtypes. These results permit us to conclude that SPECT imaging of (R,R)-[123I]IQNB localization can potentially be used to quantitate changes in the M2 subtype in a disease state within a brain region for which the ratio M2/M1 is sufficiently high in normal individuals.

Alzheimer Disease↗