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J J Frost

Publications and source records attributed to J J Frost.

At least 37 records · Page 2Linked to original sources
PubMed1994

In vivo labeling of nicotinic cholinergic receptors in brain with [3H]cytisine.

[3H]Cytisine was evaluated as an in vivo ligand for the nicotinic cholinergic receptor (nAchR) in mouse brain. The tracer was injected intravenously, and radioactivity in brain regions was analyzed. Radioactivity peaked in the brain at 30 minutes. It was highest in the thalamus, intermediate in the superior colliculi, prefrontal cortex and hippocampus, and low in the cerebellum. Pretreatment with unlabeled cytisine inhibited binding in the thalamus, but not in the cerebellum. Binding was displaced by l-nicotine, but not by d-nicotine or dexetimide. The results suggest that cytisine, appropriately labeled with a positron emitting radionuclide, may be useful for study of nicotinic cholinergic receptors in humans by emission computed tomography.

Alkaloids↗
PubMed1994

SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates: I. Kinetic modeling of single bolus experiments.

The aim of this work was to study the feasibility and reproducibility of in vivo measurement of benzodiazepine receptors with single photon emission computerized tomography (SPECT) in the baboon brain. Arterial and brain regional activities were measured for 420 min in three baboons after single bolus injection of the benzodiazepine antagonist [123I]iomazenil. Data were fit to a three-compartment model to derive the regional binding potential (BP), which corresponds to the product of the receptor density, (Bmax) and affinity (1/KD). Regional BP values (from 114 in striatum to 241 in occipital) were in good agreement with values predicted from in vitro studies. Constraining the regional volume of distribution of the nondisplaceable compartment to the value measured during tracer constant infusion experiments in baboons (Laruelle et al., 1993) improved the identifiability of the rate constants. Each experiment was repeated to investigate the reproducibility of the measurement. The regional average reproducibility was 10 +/- 5%, expressed as coefficient of variation (CV). Results of equilibrium analysis at peak uptake were in good agreement with results of kinetic analysis. Empirical counts ratio methods were found to be poorly sensitive to benzodiazepine receptor density. These studies suggest the feasibility of quantitative measurement of benzodiazepine receptors by kinetic analysis of SPECT data and the inadequacy of empirical methods of analysis, such as counts ratios, to evaluate differences in receptor density.

Animals↗
PubMed1993

Single photon emission tomography measurement of benzodiazepine receptor number and affinity in primate brain: a constant infusion paradigm with [123I]iomazenil.

Benzodiazepine receptor number and affinity were measured in vivo with single photon emission tomography (SPECT). Following an initial bolus injection, the radiotracer [123I]iomazenil was infused at a constant rate for 5 to 8 h. This procedure induced a state of sustained equilibrium at the receptor level. Nondisplaceable activity was measured after injection of a receptor saturating dose of flumazenil. Experiments performed at high and low specific activity permitted estimation of an equilibrium binding affinity constant of 0.47 nM and a maximum binding capacity of 127 nM in occipital cortex.

Animals↗
PubMed1993

Decreased hippocampal muscarinic cholinergic receptor binding measured by 123I-iododexetimide and single-photon emission computed tomography in epilepsy.

Regional binding of 123I-iododexetimide, a muscarinic acetylcholine receptor antagonist, was measured in vivo in the temporal lobes of 4 patients with complex partial seizures using single-photon emission computed tomography. In the anterior hippocampus ipsilateral to the electrical focus, 123I-iododexetimide binding was decreased by 40 +/- 9% (mean +/- SD, p < 0.01) compared with the contralateral hippocampus; 123I-iododexetimide binding in other temporal lobe regions was symmetrical. The data indicate a regionally specific change of muscarinic acetylcholine receptor in anterior hippocampus in complex partial seizures of temporal lobe origin.

Adult↗
PubMed1993

Positron emission tomographic imaging of the dopamine transporter with 11C-WIN 35,428 reveals marked declines in mild Parkinson's disease.

Parkinson's Disease (PD) is characterized by a selective loss of nigrostriatal dopaminergic neurons that results in a marked reduction of dopaminergic nerve terminals in the striatum. Recently, 11C-WIN 35,428, a cocaine analogue that specifically labels the dopamine transporter, was developed and can be used to label dopaminergic nerve terminals in vivo by positron emission tomography. In healthy control subjects, binding of 11C-WIN 35,428 is highest in the striatum. In addition, 2 symmetrical focal areas of low binding were observed in the midbrain. The cerebellum functioned as an appropriate region for nonspecific binding. The binding of 11C-WIN 35,428 in patients with PD (Hoehn-Yahr II) was compared with that in healthy control subjects by using the (region-cerebellum)/cerebellum ratio for data acquired 34 to 82 minutes after injection. In control subjects, this ratio varied, at approximately 2, in the striatum. In patients with PD, binding in the posterior putamen was reduced by 78%, whereas the anterior putamen and the caudate nucleus showed a reduction of 59 and 39%, respectively. The reduction in 11C-WIN 35,428 binding was highest in the midbrain (84%). The high specific/nonspecific binding ratio and the pronounced reduction in binding in mild PD may permit detection of even earlier stages of PD or presymptomatic individuals with dopaminergic cell loss.

Biomarkers↗
PubMed1993

Measurement of benzodiazepine receptor number and affinity in humans using tracer kinetic modeling, positron emission tomography, and [11C]flumazenil.

Kinetic methods were used to obtain regional estimates of benzodiazepine receptor concentration (Bmax) and equilibrium dissociation constant (Kd) from high and low specific activity (SA) [11C]flumazenil ([11C] Ro 15-1788) positron emission tomography studies of five normal volunteers. The high and low SA data were simultaneously fit to linear and nonlinear three-compartment models, respectively. An additional inhibition study (pretreatment with 0.15 mg/kg of flumazenil) was performed on one of the volunteers, which resulted in an average gray matter K1/k2 estimate of 0.68 +/- 0.08 ml/ml (linear three-compartment model, nine brain regions). The free fraction of flumazenil in plasma (f1) was determined for each study (high SA f1: 0.50 +/- 0.03; low SA f1: 0.48 +/- 0.05). The free fraction in brain (f2) was calculated using the inhibition K1/k2 ratio and each volunteer's mean f1 value (f2 across volunteers = 0.72 +/- 0.03 ml/ml). Three methods (Methods I-III) were examined. Method I determined five kinetic parameters simultaneously [K1, k2, k3 (= konf2Bmax), k4, and konf2/SA] with no priori constraints. An average kon value of 0.030 +/- 0.003 nM-1 min-1 was estimated for receptor-rich regions using Method I. In Methods II and III, the konf2/SA parameter was specifically constrained using the Method I value of kon and the volunteer's values of f2 and low SA (Ci/mumol). Four parameters were determined simultaneously using Method II. In Method III, K1/k2 was fixed to the inhibition value and only three parameters were estimated. Method I provided the most variable results and convergence problems for regions with low receptor binding. Method II provided results that were less variable but very similar to the Method I results, without convergence problems. However, the K1/k2 ratios obtained by Method II ranged from 1.07 in the occipital cortex to 0.61 in the thalamus. Fixing the K1/k2 ratio in Method III provided a method that was physiologically consistent with the fixed value of f2 and resulted in parameters with considerably lower variability. The average Bmax values obtained using Method III were 100 +/- 25 nM in the occipital cortex, 64 +/- 18 nM in the cerebellum, and 38 +/- 5.5 nM in the thalamus; the average Kd was 8.9 +/- 1.0 nM (five brain regions).

Adult↗
PubMed1993

Receptor imaging by PET and SPECT: focus on the opiate receptor.

Receptor imaging by PET and SPECT 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. Clinical applications of mu opiate receptor imaging are discussed for epilepsy, Alzheimer's disease and dementia.

Alzheimer Disease↗
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↗