PubMed Health⌕ Search

Biomedical subjects

J J Frost

Publications and source records attributed to J J Frost.

At least 19 recordsLinked to original sources
PubMed1992

In vivo binding of N1'-([11C]methyl)naltrindole to delta-opioid receptors in mouse brain.

The regional distribution of N1'-([11C]methyl)naltrindole ([11C]MeNTI) in vivo in mouse brain correlates with established delta opioid receptor densities in vitro. [11C]MeNTI binding is blocked by naltrindole, a delta antagonist, but not by cyprodime, a mu antagonist, of by (+/-)-U50,488, a kappa agonist. Thus, [11C]MeNTI selectively labels central delta opioid receptors in vivo in mouse, and shows promise for positron emission tomography studies of delta sites in human brain.

Animals↗
PubMed1992

Imaging muscarinic cholinergic receptors in human brain in vivo with Spect, [123I]4-iododexetimide, and [123I]4-iodolevetimide.

A method to image muscarinic acetylcholine receptors (muscarinic receptors) noninvasively in human brain in vivo was developed using [123I]4-iododexetimide ([123I]IDex), [123I]4-iodolevetimide ([123I]ILev), and single photon emission computed tomography (SPECT). [123I]IDex is a high-affinity muscarinic receptor antagonist. [123I]ILev is its pharmacologically inactive enantiomer and measures nonspecific binding of [123I]IDex in vitro. Regional brain activity after tracer injection was measured in four young normal volunteers for 24 h. Regional [123I]IDex and [123I]ILev activities were correlated early after injection, but not after 1.5 h. [123I]IDex activity increased over 7-12 h in neocortex, neostriatum, and thalamus, but decreased immediately after the injection peak in cerebellum. [123I]IDex activity was highest in neostriatum, followed in rank order by neocortex, thalamus, and cerebellum. [123I]IDex activity correlated with muscarinic receptor concentrations in matching brain regions. In contrast, [123I]ILev activity decreased immediately after the injection peak in all brain regions and did not correspond to muscarinic receptor concentrations. [123I]IDex activity in neocortex and neostriatum during equilibrium was six to seven times higher than [123I]ILev activity. The data demonstrate that [123I]IDex binds specifically to muscarinic receptors in vivo, whereas [123I]ILev represents the nonspecific part of [123I]IDex binding. Subtraction of [123I]ILev from [123I]IDex images on a pixel-by-pixel basis therefore reflects specific [123I]IDex binding to muscarinic receptors. Owing to its high specific binding, [123I]IDex has the potential to measure small changes in muscarinic receptor characteristics in vivo with SPECT. The use of stereoisomerism directly to measure nonspecific binding of [123I]IDex in vivo may reduce complexity in modeling approaches to muscarinic acetylcholine receptors in human brain.

Adult↗
PubMed1992

Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects.

Accuracy in in vivo quantitation of brain function with positron emission tomography (PET) has often been limited by partial volume effects. This limitation becomes prominent in studies of aging and degenerative brain diseases where partial volume effects vary with different degrees of atrophy. The present study describes how the actual gray matter (GM) tracer concentration can be estimated using an algorithm that relates the regional fraction of GM to partial volume effects. The regional fraction of GM was determined by magnetic resonance imaging (MRI). The procedure is designated as GM PET. In computer simulations and phantom studies, the GM PET algorithm permitted a 100% recovery of the actual tracer concentration in neocortical GM and hippocampus, irrespective of the GM volume. GM PET was applied in a test case of temporal lobe epilepsy revealing an increase in radiotracer activity in GM that was undetected in the PET image before correction for partial volume effects. In computer simulations, errors in the segmentation of GM and errors in registration of PET and MRI images resulted in less than 15% inaccuracy in the GM PET image. In conclusion, GM PET permits accurate determination of the actual radiotracer concentration in human brain GM in vivo. The method differentiates whether a change in the apparent radiotracer concentration reflects solely an alteration in GM volume or rather a change in radiotracer concentration per unit volume of GM.

Algorithms↗
PubMed1992

Receptor imaging by positron emission tomography and single-photon emission computed tomography.

Positron emission tomography (PET) has been used primarily to measure regional brain metabolism and blood flow. Single-photon emission computed tomography (SPECT) also can be used to measure brain perfusion. Receptor imaging by PET and SPECT, however, offers distinctive advantages over the more established flow/metabolism imaging methods, including improved chemical specificity and improved sensitivity in detecting changes in disease. Radioligands are available for PET and SPECT imaging of many neuroreceptors, including the opiate receptor, the dopamine receptor, and the muscarinic cholinergic receptor. A new focus of interest is the imaging and quantification of presynaptic neurotransmitter reuptake sites.

Brain↗
PubMed1991

Physostigmine in Alzheimer's disease: effects on cognitive functioning, cerebral glucose metabolism analyzed by positron emission tomography and cerebral blood flow analyzed by single photon emission tomography.

The effect of acute, intravenous administration of physostigmine on measures of brain activity and cognitive functioning were investigated in 14 patients with Alzheimer's disease. Regional cerebral glucose metabolism was assessed using (18F)-fluoro-2-deoxy-D-glucose and positron emission tomography, and cerebral blood flow was assessed using 123I-iodoamphetamine single photon emission tomography. Although physostigmine enhanced cerebral blood flow in most patients, only one patient showed significant clinical improvement. This patient, however, also showed a very pronounced improvement in cerebral glucose metabolism. It is concluded that these preliminary findings hold considerable promise for our appreciation of the pathophysiology of dementing illness as well as our understanding of centrally acting compounds of interest in Alzheimer's disease.

Aged↗
PubMed1991

Epilepsy.

As surgical treatments for adult and pediatric forms of epilepsy have become more refined, methods for noninvasive localization of epileptogenic foci have become increasingly important. Detection of focal brain metabolic or flow abnormalities is now well recognized as an essential step in the presurgical evaluation of many patients with epilepsy. Positron emission tomography (PET) scanning is most beneficial when used in the context of the total clinical evaluation of patients, including scalp EEG, invasive EEG, neuropsychologic testing, etc. Metabolic PET studies also give insight into pathophysiologic mechanisms of epilepsy. The dynamic nature of the interictal hypometabolism observed with 18[F]FDG in some patients suggests that excitatory or inhibitory neurotransmitters and their receptors may be involved. An exciting current application of PET scanning is the use of tracers for neurotransmitter receptors in the study of epilepsy patients. Mu and non-mu opiate receptors have been extensively studied and are beginning to give new insights into this disorder. Increased labeling of mu receptors in temporal neocortex using 11C-carfentanil has been demonstrated and, in some patients, supplements the clinical localization information from 18[F]FDG studies. Increased mu opiate receptor number or affinity is thought to play a role in anticonvulsant mechanisms. Specificity of increased mu receptors is supported by the absence of significant changes in non-mu opiate receptors. Other brain receptors are also of interest for future studies, particularly those for excitatory neurotransmitters. Combined studies of flow, metabolism, and neuroreceptors may elucidate the factors responsible for initiation and termination of seizures, thus improving patient treatment.

Adult↗
PubMed1990

Localization of peripheral cholecystokinin receptors in vivo using the cholecystokinin antagonist [3H](+/-)-MK-329.

Cholecystokinin (CCK) regulates various gastrointestinal functions through specific receptors. The mechanisms responsible for disorders of these functions could be elucidated by non-invasively localizing CCK receptors and quantifying their number in vivo. MK-329 is a highly selective and very high affinity antagonist at the peripheral CCK receptor. We investigated the in vivo binding of [3H](+/-)-MK-329 in mice to determine if binding to CCK receptors could be detected after systemic administration of the tracer. The uptake of [3H](+/-)-MK-329 increased in the pancreas from 5 min to 4 h after administration. The binding was saturable, stereospecific, and more than 80% specific. A total/non-specific binding ratio of 43 was reached at 8 h post-injection. The pancreas was the only organ where specific binding could be detected. Our results suggest that MK-329 labeled with a positron emitter such as C-11 could be used with positron emission tomography to image and quantify peripheral CCK receptors in man.

Animals↗
PubMed1990

Detection and quantification of opiate receptors in man by positron emission tomography. Potential applications to the study of pain.

Opiate receptors in the brain are the target of endogenous opioids and of exogenous synthetic opiates. It is well established that these receptors play a major role in the modulation of pain perception. With positron emission tomography (PET) and the appropriate radioligands, it is now possible to image and quantify neuroreceptors in vivo. We used 11C-diprenorphine and the extremely potent mu opiate receptor agonist 11C-carfentanil to image the distribution of opiate receptors in the human brain and to quantify their density, affinity, and occupancy. Several important methodological aspects of the in vivo opiate receptor labeling with PET in relation to the study of pain are considered in this paper. Monitoring receptor occupancy by opiate drugs as a function of pain relief has the potential to reveal better ways to treat pain.

Humans↗
PubMed1990

Comparison of [11C]diprenorphine and [11C]carfentanil binding to opiate receptors in humans by positron emission tomography.

The kinetics and regional distribution of [11C]carfentanil, a mu-selective opiate receptor agonist, and [11C]diprenorphine, a nonselective opiate receptor antagonist, were compared using paired positron emission tomography studies in two normal volunteers. Kinetics of total radioactivity (counts/mCi/pixel) was greater for [11C]diprenorphine than [11C]carfentanil in all regions. [11C]Carfentanil binding (expressed as the total/nonspecific ratio) reached near equilibrium at approximately 40 min, whereas [11C]diprenorphine showed a linear increase until approximately 60 min. Kinetics of specific binding demonstrated significant dissociation of [11C]carfentanil from opiate receptors, whereas little dissociation of [11C]diprenorphine was observed during the 90-min scan session. Regional distributions of [11C]carfentanil and [11C]diprenorphine were qualitatively and quantitatively different: Relative to the thalamus (a region with known predominance of mu-receptors), [11C]diprenorphine displayed greater binding in the striatum and cingulate and frontal cortex compared to [11C]carfentanil, consistent with labeling of additional, non-mu sites by [11C]diprenorphine. We conclude from these studies that [11C]diprenorphine labels other opiate receptor subtypes in addition to the mu sites selectively labeled by [11C]carfentanil. The nonselective nature of diprenorphine potentially limits its usefulness in defining abnormalities of specific opiate receptor subtypes in various diseases. Development of selective tracers for the delta- and kappa-opiate receptor sites, or alternatively use of unlabeled inhibitors to differentially displace mu, delta, and kappa subtypes, will help offset these limitations.

Adult↗
PubMed1989

In vivo labeling of central benzodiazepine receptors with the partial inverse agonist [3H]Ro 15-4513.

Ro 15-4513 is an imidazobenzodiazepine and a partial inverse agonist at the central benzodiazepine receptors (BZDr). It has been shown to antagonize behavioral and biochemical effects of ethanol. In vivo binding of [3H]Ro 15-4513 was evaluated in mouse brain. After intravenous injection [3H]Ro 15-4513 was readily taken up by the brain and distributed to brain areas enriched in benzodiazepine receptors. Binding was specific for central BZDr, saturable and reversible. A high degree of specific binding, relative to non-specific binding, was achieved. Analysis of dissociation kinetics revealed that [3H]Ro 15-4513 was retained significantly longer in hippocampus compared to other brain regions. In view of the known distribution of benzodiazepine receptor subtypes, this suggests that, in vivo, [3H]Ro 15-4513 has a higher affinity for benzodiazepine receptors type II and may explain quantitative differences in the regional distribution of this ligand compared to the antagonist [3H]Ro 15-1788. We conclude from these studies that Ro 15-4513 is a suitable ligand for in vivo studies of benzodiazepine receptors. Labeled with a positron-emitting isotope, it could be used with positron emission tomography to study BZDr in man under a variety of conditions.

Animals↗
PubMed1989

Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist.

A series of halogenated racemic analogues of dexetimide (1) was synthesized and their affinity for the muscarinic cholinergic receptor measured. One analogue, 4-iododexetimide (21), was efficiently labeled with 125I and 123I at high specific activity. In vitro binding studies and in vivo biodistribution studies suggest that 123I-labeled 21 may be useful for imaging muscarinic cholinergic receptors in the living human brain with single photon emission computed tomography.

Animals↗
PubMed1989

Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography.

[11C]-Carfentanil is a high affinity opiate agonist that can be used to localize mu opiate receptors in humans by positron emission tomography (PET). A four-compartment model was used to obtain quantitative estimates of rate constants for receptor association and dissociation. PET studies were performed in five normal subjects in the absence and presence of 1 mg/kg naloxone. Arterial plasma concentration of [11C]-carfentanil and its labeled metabolites were determined during each PET study. The value of k3/k4 = Bmax/kD was determined for each subject in the presence and absence of naloxone. There was a significant reduction in the value of k3/k4 from 3.4 +/- 0.92 to 0.26 +/- 0.13 in the thalamus (p less than 0.01) and from 1.8 +/- 0.33 to 0.16 +/- 0.065 in the frontal cortex (p less than 0.001). Mean values of frontal cortex/occipital cortex and thalamus/occipital cortex ratios were determined for the interval 35-70 min after injection when receptor binding is high relative to nonspecific binding. The relationship between the measured region/occipital cortex values and the corresponding values of k3/k4 in the presence and absence of naloxone was: regions/occipital cortex = 0.95 + 0.74 (k3/k4) with r = 0.98 (n = 20). Simulation studies also demonstrated a linear relationship between the thalamus/occipital cortex or frontal cortex/occipital cortex ratio and k3/k4 for less than twofold increases or decreases in k3/k4. Simulation studies in which thalamic blood flow was varied demonstrated no significant effect on the region/occipital cortex ratio at 35-70 min for a twofold increase or fourfold decrease in blood flow. Therefore, the region/occipital cortex ratio can be used to quantitate changes in k3/k4 when tracer kinetic modeling is not feasible.

Adult↗
PubMed1988

Mu-opiate receptors measured by positron emission tomography are increased in temporal lobe epilepsy.

Neurochemical studies in animal models of epilepsy have demonstrated the importance of multiple neurotransmitters and their receptors in mediating seizures. The role of opiate receptors and endogenous opioid peptides in seizure mechanisms is well developed and is the basis for measuring opiate receptors in patients with epilepsy. Patients with complex partial seizures due to unilateral temporal seizure foci were studied by positron emission tomography using 11C-carfentanil to measure mu-opiate receptors and 18F-fluoro-deoxy-D-glucose to measure glucose utilization. Opiate receptor binding is greater in the temporal neocortex on the side of the electrical focus than on the opposite side. Modeling studies indicate that the increase in binding is due to an increase in affinity or the number of unoccupied receptors. No significant asymmetry of 11C-carfentanil binding was detected in the amygdala or hippocampus. Glucose utilization correlated inversely with 11C-carfentanil binding in the temporal neocortex. Increased opiate receptors in the temporal neocortex may represent a tonic anticonvulsant system that limits the spread of electrical activity from other temporal lobe structures.

Adolescent↗