In vivo imaging of dopamine reuptake sites in the primate brain using single photon emission computed tomography (SPECT) and iodine-123 labeled RTI-55.
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Animals↗
Biomedical subjects
R F Dannals
Publications and source records attributed to R F Dannals.
[123/125I]RTI-55, an in vivo label for the serotonin transporter.
[123I]RTI-55, an iodinated derivative of the cocaine analog 3 beta-phenyltropane-2 beta-carboxylic acid methyl ester, was evaluated as an agent for in vivo labeling of the serotonin transporter. Labeling of the precursor of RTI-55 with I-123 was efficient and yielded a high specific activity product. After intravenous injection of [123I]RTI-55 into rats, the tracer accumulated in regions with high densities of serotonin and dopamine uptake sites. The distribution of [123I]RTI-55 binding in areas rich in serotonin uptake sites correlated with [3H]serotonin uptake measured in vitro in the same regions. Specific [123I]RTI-55 binding to serotonin uptake sites was inhibited by paroxetine but not by GBR 12,909. Treatment of rats with neurotoxic doses of fenfluramine caused decreases of 66% (in the hypothalamus) to 83% (in the superior colliculi) of specific [125I]RTI-55 binding in all areas except in the striatum and the olfactory tubercles (regions rich in dopamine transporters). These results indicate that [123/125I]RTI-55 binds, although not selectively, to the serotonin transporter in vivo. Furthermore, they suggest that [123I]RTI-55 holds promise as a SPECT imaging agent for the study of the serotonin transporter in humans in health and disease.
Animals↗
In vivo studies of [125I]iodobenzamide and [11C]iodobenzamide: a ligand suitable for positron emission tomography and single photon emission tomography imaging of cerebral D2 dopamine receptors.
Iodobenzamide (IMB) labeled with either [11C] or [125I] was studied in mice and baboons. Pharmacological studies demonstrated an in vivo binding profile compatible with D2 dopamine receptors. Mouse biodistribution studies with both [11C]IMB and [125I]IMB showed a similar brain distribution of radioactivity. Mouse [125I]IMB studies with amphetamine and reserpine pretreatment suggested that IMB may be less susceptible to endogenous dopamine competition for D2 receptor binding in vivo as compared to raclopride. Preliminary baboon studies showed haloperidol competition for IMB binding sites.
Animals↗
Factor analysis of regional cerebral glucose metabolic rates in healthy men.
Cerebral glucose utilization measured with fluorine-18-fluoro-2-deoxy-D-glucose is characterized by considerable variability both among different persons and for the same person examined on different occasions. The goal of this study was to explore whether some regions of the brain were more variable than others with respect to glucose utilization and whether there was a pattern in their covariance. The global and regional cerebral utilization of glucose was measured in 12 healthy young volunteers on 3 or 4 occasions. In all, 24 regions were examined. The interrelation of the glucose utilization rates of the brain regions was investigated by factor analysis of the metabolic rates. Some 70% of the total variance was attributable to only 1 factor, while 80% of the total variance could be attributed to 2 factors. Regions making up the first factor were the frontal and temporal cortex, cingulate gyrus, caudate nucleus, thalamus and putamen. These regions are functionally related to the limbic system. Regions of the second factor were the parietal cortex, occipital cortex and cerebellum, regions more clearly related to sensory and motor functions. The 2-factor pattern was highly reproducible, being found with different algorithms for factor extraction and rotation. Under resting conditions, the variance of cerebral metabolism seems to be primarily related to regions which are closely involved with the limbic system. Cortical regions involved primarily in motor and sensory functions have less influence on the variance.
Adult↗
Synthesis and biodistribution of a new radiotracer for in vivo labeling of serotonin uptake sites by PET, cis-N,N-[11C]dimethyl-3-(2',4'-dichlorophenyl)-indanamine (cis-[11C]DDPI).
A new PET radiotracer for in vivo labeling of serotonin (5-HT) uptake sites, cis-N,N-[11C]dimethyl-3-(2',4'-dichlorophenyl)-indanamine, cis-[11C]DDPI, was synthesized and its biological behavior was studied. The radiosynthesis of cis-[11C]DDPI was performed by N-methylation of cis-N-methyl-3-(2',4'-dichlorophenyl)-indanamine with [11C]iodomethane. The average radiochemical yield was approx. 8%, with an average specific activity of 600 mCi/mumol. Following intravenous administration, cis-[11C]DDPI accumulated in mouse brain regions rich in 5-HT uptake sites, such as olfactory tubercles, hypothalamus and frontal cortex. Following pre-injection of 1 mg/kg of paroxetine, a high affinity 5-HT uptake blocker, the binding of cis-[11C]DDPI in the olfactory tubercles, hypothalamus and frontal cortex was decreased by 23, 25 and 16%; this corresponds to 73, 82 and 59% of the specific binding in these regions. These results suggest that the accumulation of cis-[11C]DDPI in the tissues rich in 5-HT sites is a result of specific binding of cis-[11C]DDPI to 5-HT uptake sites. Due to the relatively high non-specific uptake and slow clearance of this compound from non-specific binding sites, the ratio between specific and non-specific binding increased slowly with time, reaching 1.5:1 at 60 min after injection.
Animals↗
The influence of biological and technical factors on the variability of global and regional brain metabolism of 2-[18F]fluoro-2-deoxy-D-glucose.
This study investigated the influence of biological and technical factors on variations of global and regional cerebral metabolic rate of glucose (CMRglc) measured with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG). Twelve male volunteers (22-40 years) were investigated on three or four occasions for a total of 42 studies. We calculated the variance/covariance of the following parameters: CMRglc, six parameters of the blood clearance of [18F]FDG, hour of injection, peak time of blood radioactivity, and six components of the operational equation (nonradioactive blood glucose concentration, brain radioactivity, two integrals, numerator, and denominator). There was correlation among these six components, except for nonradioactive blood glucose. However, the correlation between the CMRglc and the individual components of the operational equation was poor. The inter- and intrapersonal CMRglc coefficients of variations were 13.8 and 7.1%, respectively. In contrast, coefficients of variations of the numerator and denominator of the operational equation were 34.6 and 32.6%, respectively, and were always in the same direction. No correlation was found between CMRglc and the technical factors in the numerator and denominator of the operational equation. Factor analysis disclosed that a single factor was responsible for 70% of the variance. This factor included caudate, putamen, thalamus, frontal cortex, temporal cortex, and cingulate gyrus. These structures are involved with multiple complex functions, from autonomic motor control to behavior and emotions. The intrinsic metabolic variability of these structures, along with the basal metabolic processes that are continuously going on in the brain, may be the best explanation for the variance encountered in our investigation.
Adult↗
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↗
Dopamine transporter imaging with novel, selective cocaine analogs.
RTI-121 and RTI-122 are 3 beta-substituted phenyltropane analogs of cocaine that have high, selective binding affinity for dopamine transporters. [123I]RTI-121 and [123I]RTI-122 bind to dopamine transporters in vivo after intravenous administration and permit imaging of the transporters.
Animals↗
Effects of vasopressin on blood-brain transfer of methionine in dogs.
We used a simplified probe detection system for positron-emitting radionuclides in order to measure blood-brain barrier transport of amino acids in anesthetized dogs. Plasma and brain time-activity curves were recorded after intravenous bolus injection of L-[11C]methionine before and after administration of 1 microgram of vasopressin. Three-compartment models with three or four transfer coefficients were used to derive the kinetics of L-[11C]methionine uptake in brain. The blood-brain clearance of the tracer (K1) was 0.075 ml ml-1 min-1 before and 0.041 ml ml-1 min-1 after injection of vasopressin. The partition volume and the initial distribution (plasma) volume of methionine were unchanged and within the expected limits. The net accumulation rate of methionine (K), estimated by both the four-parameter (kinetic) and three-parameter (graphic) approaches, decreased after vasopressin injection in all six studies.
Animals↗
Paralimbic frontal lobe hypometabolism in depression associated with Huntington's disease.
We measured regional cerebral glucose metabolism using 2-[18F]-fluoro-2-deoxy-D-glucose and positron emission tomography in depressed and nondepressed patients with early Huntington's disease (HD), compared with appropriately matched controls. Caudate, putamen, and cingulate metabolism was significantly lower in patients with HD than in control subjects, independent of mood state. Orbital frontal-inferior prefrontal cortex hypometabolism, however, differentiated depressed patients from both nondepressed patients and normal controls. These findings implicate selective dysfunction of the paralimbic regions of the frontal lobes in the mood disorder of HD. The metabolic pattern is similar to that in depression associated with Parkinson's disease, suggesting that the integrity of pathways linking paralimbic frontal cortex and the basal ganglia may be integral to the normal regulation of mood.
Affect↗
Positron emission tomography evaluation of dopamine D-2 receptors in adults with Tourette syndrome.
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Humans↗
Quantification of mu and non-mu opiate receptors in temporal lobe epilepsy using positron emission tomography.
Alterations in a variety of neurotransmitter systems have been identified in experimental models of epilepsy and in brain tissue from patients with intractable temporal lobe seizures. The availability of new high-affinity radioligands permits the study of some neuroreceptors in vivo with positron emission tomography (PET). We previously characterized the in vivo binding of 11C-carfentanil, a potent and selective mu opiate receptor agonist, and described increases in 11C-carfentanil binding in the temporal neocortex of patients with unilateral temporal lobe epilepsy. These studies have been extended to 11C-diprenorphine, which labels mu, kappa, and delta opiate receptor subtypes. Paired measurements of opiate receptor binding were performed with PET using 11C-carfentanil and 11C-diprenorphine in patients with unilateral temporal lobe seizures. Carfentanil binding, reflecting changes in mu opiate receptors, was increased in the temporal neocortex and decreased in the amygdala on the side of the epileptic focus. Diprenorphine binding, reflecting mu as well as non-mu opiate subtypes, was not significantly different among regions in the focus and nonfocus temporal lobes. Regional glucose metabolism, measured using 18F-2-fluoro-2-deoxyglucose, was decreased in the mesial and lateral aspects of the temporal lobe ipsilateral to the epileptogenic focus. The variation in pattern of carfentanil and diprenorphine binding supports a differential regulation of opiate subtypes in unilateral temporal lobe epilepsy.
Amygdala↗
Effects of atropine treatment on in vitro and in vivo binding of 4-[125I]-dexetimide to central and myocardial muscarinic receptors.
Upregulation of muscarinic cholinergic receptors (mAChR) after chronic atropine treatment has been described previously. The present study was designed to evaluate 4-iodine-125 dexetimide as an agent to determine changes in the number of mAChR. Rats were injected subcutaneously with atropine (500 mg/kg) either once or chronically, once daily for 10 days, and sacrificed 24 h later. In vitro binding assays with 4-[125I]-dexetimide showed significant increases in the number of mAChR in cerebra (21%) and ventricles (45%) after chronic atropine treatment but not after acute treatment. The affinity of binding to cerebral and ventricular mAChR declined after acute and chronic atropine treatment. In vivo studies were carried out involving intravenous injection of 4-[125I]-dexetimide 24 h after atropine treatment. Binding was markedly reduced in the brain and heart. Upregulation of mAChR, as seen in in vitro studies, could not be observed because of the remaining atropine. Occupancy of mAChR by atropine persisted as long as 7 days after one dose. The results of these studies indicate that 4-[125I]-dexetimide binding reflects the effects of atropine on central and peripheral muscarinic cholinergic receptors in vitro and in vivo.
Animals↗
In vivo biodistribution of two [18F]-labelled muscarinic cholinergic receptor ligands: 2-[18F]- and 4-[18F]-fluorodexetimide.
Two [18F]-labelled analogues of the potent muscarinic cholinergic receptor (m-AChR) antagonist, dexetimide, were evaluated as potential ligands for imaging m-AChR by positron emission tomography (PET). Intravenous administration of both 2-[18F]- or 4-[18F]-fluorodexetimide resulted in high brain uptake of radioactivity in mice. High binding levels were observed in m-AChR rich areas, such as cortex and striatum, with low levels in the receptor-poor cerebellum. Uptake of radioactivity was saturable and could be blocked by pre-administration of dexetimide or atropine. Drugs with different sites of action were ineffective at blocking receptor binding. The results indicate that both radiotracers are promising candidates for use in PET studies.
Animals↗
Radiosynthesis and evaluation of N-(3-[18F]fluoropropyl)paroxetine as a radiotracer for in vivo labeling of serotonin uptake sites by PET.
To visualize serotonin uptake sites by positron emission tomography (PET), N-(3-[18F]fluoropropyl)-paroxetine ([18F]FPP), a derivative of the selective serotonin uptake blocker paroxetine, was synthesized from 3-[18F]fluoropropyltosylate and paroxetine via a one-pot procedure. The rate of formation of [18F]FPP was a function of the ratio of the initial amount of paroxetine to that of 1,3-propanediol bistosylate with which [18F]fluoropropyltosylate was synthesized. When the reaction mixture contained an excess amount of paroxetine over that of the propyl-bistosylate, the radiosynthesis followed by HPLC purification, which took approx. 90 min, gave [18F]FPP in a radiochemical yield of approx. 8%, and in high radiochemical and chemical purity. The specific activity was 2640 +/- 360 mCi/mumol. The brain biodistribution of [18F]FPP showed no distinguishable localization in regions with high density of serotonin uptake sites such as hypothalamus or olfactory tubercles. In vitro binding assays revealed that N-fluoropropylation of paroxetine reduced the affinity for the serotonin uptake site by three orders of magnitude.
Animals↗
Radiosynthesis of sigma receptor ligands for positron emission tomography: 11C- and 18F-labeled guanidines.
A series of analogues of the potent and selective sigma receptor ligand 1,3-ditolylguanidine (DTG) were synthesized and demonstrated to have high affinity for the sigma receptor as measured by in vitro [3H]DTG displacement studies using guinea pig brain tissue. Three of these 1-aryl-3-(1-adamantyl)guanidines were radiolabeled--two with carbon-11 and one with fluorine-18. Radiochemical yields and specific activities were sufficient for these radiotracers to be used in positron emission tomography imaging of the haloperidol-sensitive sigma receptor.
Animals↗
Quantification of human opiate receptor concentration and affinity using high and low specific activity [11C]diprenorphine and positron emission tomography.
[11C]Diprenorphine, a weak partial opiate agonist, and positron emission tomography were used to obtain noninvasive regional estimates of opiate receptor concentration (Bmax) and affinity (Kd) in human brain. Different compartmental models and fitting strategies were compared statistically to establish the most reliable method of parameter estimation. Paired studies were performed in six normal subjects using high (769-5,920 Ci/mmol) and low (27-80 Ci/mmol) specific activity (SA) [11C]diprenorphine. Two subjects were studied a third time using high SA [11C]diprenorphine after a pretreatment with 1-1.5 mg/kg of the opiate antagonist naloxone. After the plasma radioactivity was corrected for metabolites, the brain data were analyzed using a three-compartment model and nonlinear least-squares curve fitting. Linear differential equations were used to describe the high SA (low receptor occupancy) kinetics. The k3/k4 ratio varied from 1.0 +/- 0.2 (occipital cortex) to 8.6 +/- 1.6 (thalamus). Nonlinear differential equations were used to describe the low SA (high receptor occupancy) kinetics and the curve fits provided the konf2 product. The measured free fraction of [11C]diprenorphine in plasma (f1) was 0.30 +/- 0.03, the average K1/k2 ratio from the two naloxone studies was 1.1 +/- 0.2, and the calculated free fraction of [11C]diprenorphine in the brain (f2) was 0.3. Using the paired SA studies, the estimated kinetic parameters, and f2, separate estimates of Bmax and Kd were obtained. Bmax varied from 2.3 +/- 0.5 (occipital cortex) to 20.6 +/- 7.3 (cingulate cortex) nM. The average Kd (eight brain regions) was 0.85 +/- 0.17 nM.
Adult↗
Global and regional cerebral metabolic rate of 2-[18F]fluoro-2-deoxy-D-glucose in the presence of ofloxacin, a gamma-aminobutyric acid a receptor antagonist.
We investigated the effects of ofloxacin, a new antibacterial quinolone gamma-aminobutyric acid A receptor antagonist, on the global and regional cerebral metabolic rates of glucose (cMRgl). Twelve healthy normal male volunteers (mean age, 26.7 years) were studied in a double-blind, placebo-controlled protocol of 11 days' duration. Results of a total of 42 positron emission tomography studies were obtained for these subjects: 12 base line, 18 during placebo, and 12 during ofloxacin administration. The conditions under which repeat positron emission tomography studies of the same subject were performed were reproduced as closely as possible. cMRgl was measured in 24 brain regions. The global cMRgl for base line, placebo, and ofloxacin were 8.82 +/- 1.17, 8.24 +/- 1.17, and 8.79 +/- 1.18 mg/min/100 g, respectively (mean +/- 1 standard deviation). The mean global differences between base line and placebo and between ofloxacin and placebo were 5.1 and 6.6%, respectively. Analysis of variance of both the global and the regional cMRgl showed no statistical difference between base-line, placebo, and ofloxacin studies. Variations in cMRgl found in this study were not related to the presence of ofloxacin. Results of our study demonstrate that ofloxacin does not increase or decrease cMRgl beyond the limits of variability of the study.
Adult↗