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Biomedical subjects

R B Innis

Publications and source records attributed to R B Innis.

At least 19 recordsLinked to original sources
PubMed2004

Radiation dosimetry estimates for the PET serotonin transporter probe 11C-DASB determined from whole-body imaging in non-human primates.

The radiotracer 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile labelled in the N-methyl position (11C-DASB) is a selective radioligand for the in vivo quantification of serotonin transporters (SERTs) using positron emission tomography (PET). The current study quantified the distribution of activity in two rhesus monkeys after the injection of approximately 333 MBq (9 mCi) 11C-DASB. Whole-body images were acquired at 22 time points for a total of 120 min following injection of the radioligand. Source organs were identified at each time point from both tomographic images (using multiple regions of interest on each tomograph for each organ) and a single planar image (using a single region of interest for each organ). The peak activities in planar images in the five identified source organs (expressed as per cent injected dose (ID)) were lungs (24% ID at 1.5 min), kidneys (6.5% ID at 4 min), liver (8% ID at 3 min), brain (4% ID at 5 min) and spleen (0.42% ID at 3 min). Mono-exponential fitting of activity overlying the bladder suggested that approximately 14% of activity was excreted via the urine. The radiation burden to the body was calculated from residence times of these source organs and then scaled to corresponding human values. The calculated effective dose from tomographic and planar images was 6.0 and 6.4 microGy x MBq(-1) (22.3 and 23.7 mrad x mCi(-1)), respectively. The planar analysis was much easier to perform, and generally yielded slightly higher (i.e., more conservative) estimates of radiation burden than the tomographic analysis. The estimated radiation burden of 11C-DASB is relatively modest and would allow multiple scans per research subject per year.

Aniline Compounds↗
PubMed2001

Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers.

Nicotine and other constituents of tobacco smoke elevate dopamine (DA) and serotonin (5-HT) levels in brain and may cause homeostatic adaptations in DA and 5-HT transporters. Since sex steroids alter DA and 5-HT transporter expression, the effects of smoking on DA and 5-HT transporter availability may differ between sexes. In the present study, DA and 5-HT transporter availabilities were quantitated using single photon emission computed tomography (SPECT) imaging approximately 22 h after bolus administration of [123I]beta-CIT, an analog of cocaine which labels DA and 5-HT transporters. Forty-two subjects including 21 pairs of age-, race-, and gender-matched healthy smokers and nonsmokers (12 female and 9 male pairs) were imaged. Regional uptake was assessed by the outcome measures, V3", which is the ratio of specific (i.e., ROI-cerebellar activity) to nondisplaceable (cerebellar) activity, and V3, the ratio of specific to free plasma parent. Overall, striatal and diencephalic [123I]beta-CIT uptake was not altered by smoking, whereas brainstem [123I]beta-CIT uptake was modestly higher (10%) in smokers vs. nonsmokers. When subgrouped by sex, regardless of smoking status, [123I]beta-CIT uptake was higher in the striatum (10%), diencephalon (15%), and brainstem (15%) in females vs. males. The sex*smoking interaction was not significant in the striatum, diencephalon, or brainstem, despite the observation of 20% higher brainstem [123I]beta-CIT uptake in male smokers vs. nonsmokers and less than a 5% difference between female smokers and nonsmokers. The results demonstrate higher DA and 5-HT transporter availability in females vs. males and no overall effect of smoking with the exception of a modest elevation in brainstem 5-HT transporters in male smokers. Although these findings are preliminary and need validation with a more selective 5-HT transporter radiotracer, the results suggest that brainstem 5-HT transporters may be regulated by smoking in a sex-specific manner.

Adult↗
PubMed2001

Reproducibility of in vivo brain measures of 5-HT2A receptors with PET and.

The test/retest reproducibility of brain measures of 5-HT2A receptors with positron emission tomography (PET) and [18F]deuteroaltanserin was examined in a group of eight healthy human subjects. PET measures of 5-HT2A receptors were obtained under an equilibrium paradigm, with a 40-min PET acquisition starting approximately at 300 min (308+/-11 min) after bolus plus constant infusion of the radiotracer. Three brain outcome measures were obtained at equilibrium, V(3) (ratio of specific brain uptake to free parent plasma concentration of radiotracer), V(3)' (ratio of specific brain uptake to total parent plasma concentration) and RT (ratio of specific to non-displaceable brain uptakes). V(3)' and RT had high test/retest reproducibility, as measured by mean intra-subject% change for cortical brain areas of 14.1 and 11.0%, respectively. They also had high reliability, as measured by mean intra-class correlation coefficients (ICC) for cortical brain areas of 0.86 and 0.88, respectively. V(3) had low test/retest reproducibility, due to high variability in the measures of free parent tracer in plasma. This study supports the feasibility of equilibrium imaging of 5-HT2A receptors with PET and [18F]deuteroaltanserin. The equilibrium imaging method with [18F]deuteroaltanserin allows a single acquisition and blood measurement to provide an image whose pixel values equal a receptor volume of distribution. Since the single image pixel values are proportional to receptor densities, the images can be used in pixel-by-pixel statistical methods, such as SPM, to assess the distribution and density of 5-HT2A receptors in neuropsychiatric disorders.

Adult↗
PubMed2001

[(123)I]beta-CIT SPECT imaging demonstrates reduced density of striatal dopamine transporters in Parkinson's disease and multiple system atrophy.

In vivo imaging of the dopamine transporter (DAT) with single photon emission computed tomography (SPECT) is a quantitative biomarker for Parkinson's disease (PD) onset and severity. This study has examined and compared the loss of striatal DAT in PD and multiple system atrophy (MSA) using [(123)I]beta-CIT SPECT imaging. One hundred and eighty-three patients (157 PD and 26 MSA) were studied. Clinical rating scales (Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale [UPDRS] scores) demonstrated that the MSA patients were more severely impaired than the PD patients. The striatal [(123)I]beta-CIT SPECT uptake was markedly reduced in both the PD and MSA groups. In addition, MSA patients showed more symmetric DAT loss compared with the PD patients, consistent with the more symmetric clinical motor dysfunction observed in MSA. While the loss of DAT was significantly reduced in all regions in both MSA and PD, comparison of the relative loss of the DAT did not significantly improve diagnostic accuracy in distinguishing between PD and MSA.

Adult↗
PubMed2001

The variable number of tandem repeats polymorphism of the dopamine transporter gene is not associated with significant change in dopamine transporter phenotype in humans.

A 40 base polymorphism of a variable number of tandem repeats (VNTR) has been described in the 3' untranslated region of the gene (SLC6A3) coding for the dopamine transporter (DAT). Despite being located in the untranslated region of the gene, this polymorphism has been associated with clinical phenotypes associated with dysregulation of dopamine transmission, such as attention deficit hyperactivity disorder and cocaine-induced paranoia. To examine the neurochemical phenotype associated with this polymorphism, we compared amphetamine-induced dopamine release (measured as displacement of the radiotracer [123I]IBZM) and DAT expression (measured with [123I]beta-CIT) in the striatum with Single Photon Computerized Emission Tomography (SPECT). Our sample included 59 subjects, 31 healthy controls and 29 patients with schizophrenia. No significant association was found between VNTR polymorphism and amphetamine-induced dopamine release or DAT density in the total sample, nor when each diagnostic group was considered separately. Thus, we did not replicate the findings of two previous studies, which had suggested that the 9 repeat allele was associated with either an increased or decreased DAT expression, albeit in different patient populations.

Adult↗
PubMed2001

Comparison of [(18)F]altanserin and [(18)F]deuteroaltanserin for PET imaging of serotonin(2A) receptors in baboon brain: pharmacological studies.

The regional distribution in brain, distribution volumes, and pharmacological specificity of the PET 5-HT(2A) receptor radiotracer [(18)F]deuteroaltanserin were evaluated and compared to those of its non-deuterated derivative [(18)F]altanserin. Both radiotracers were administered to baboons by bolus plus constant infusion and PET images were acquired up to 8 h. The time-activity curves for both tracers stabilized between 4 and 6 h. The ratio of total and free parent to metabolites was not significantly different between radiotracers; nevertheless, total cortical R(T) (equilibrium ratio of specific to nondisplaceable brain uptake) was significantly higher (34-78%) for [(18)F]deuteroaltanserin than for [(18)F]altanserin. In contrast, the binding potential (Bmax/K(D)) was similar between radiotracers. [(18)F]Deuteroaltanserin cortical activity was displaced by the 5-HT(2A) receptor antagonist SR 46349B but was not altered by changes in endogenous 5-HT induced by fenfluramine. These findings suggest that [(18)F]deuteroaltanserin is essentially equivalent to [(18)F]altanserin for 5-HT(2A) receptor imaging in the baboon.

Analysis of Variance↗
PubMed2000

Imaging serotonergic neurotransmission in depression: hippocampal pathophysiology may mirror global brain alterations.

The recent development of [carbonyl-(11)C]WAY-100635 for serotonin (5-HT)(1A) and [(18)F]setoperone and [(18)F]altanserin for 5-HT(2A) positron emission tomography receptor imaging has allowed studies of 5-HT neurotransmission in depressive disorders. The hippocampus is likely to be an important brain structure in the pathophysiology of depression because it may mediate both cognitive deficits and hypercortisolemia found in this disorder. Decreased 5-HT(1A) binding was reported in the medial temporal cortex, which receives dense 5-HT innervation, and also throughout neocortical regions. Because the 5-HT(1A) antagonist pindolol may hasten antidepressant effects of selective serotonin reuptake inhibitor medications, its receptor occupancy has been measured in both presynaptic and postsynaptic sites. The results are controversial but suggest that pindolol has preferential occupancy of somatodendritic autoreceptors in the raphe. The results of 5-HT(2A) receptors are mixed, with one showing a significant decrease in the right orbitoinsular cortex and three not detecting a significant change. The disparate findings in patients with depression almost certainly reflect the heterogeneity of the disorder, and we highlight the utility of the hippocampus as a useful target region not only to compare depressed subjects with healthy subjects but also to correlate findings with cognitive function and activity of the limbic-hypothalamic-pituitary axis system.

Atrophy↗
PubMed2000

Cyclopentadienyltricarbonylrheniumbenzazepines: synthesis and binding affinity.

Analogues of the benzazepine dopamine D1 receptor antagonist SCH-23390 incorporating the cyclo-pentadienyltricarbonyl-rhenium (CPTR) moiety were synthesized and evaluated pharmacologically. The CPTR derivatives retained affinity (0.3-2.9 nM) and D1 selectivity of the parent compound, supporting their use as neuropharmacological surrogates for 99mTc-labeled SPECT radiopharmaceuticals.

Animals↗
PubMed2000

SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder.

BACKGROUND: Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects. METHODS: A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96). RESULTS: A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex. CONCLUSIONS: Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.

Adolescent↗
PubMed2000

Imaging extrastriatal dopamine D(2) receptor occupancy by endogenous dopamine in healthy humans.

The effect of endogenous dopamine on in vivo measurement of dopamine D(2) receptors in extrastriatal regions (thalamus and temporal cortex) was evaluated with single photon emission computed tomography and the high affinity ligand [123I]epidepride by comparing the binding potential before and after acute dopamine depletion. Dopamine depletion was achieved by per-oral administration of 5.5 g/70 kg body weight alpha-methyl-para-tyrosine given in 37 h. The alpha-methyl-para-tyrosine treatment increased the binding potential significantly in the temporal cortex (13+/-15%, P=0.036) but not in the thalamus (2+/-9%). The increase of the binding potential in the temporal cortex correlated strongly with the increase of dysphoric mood evaluated by the Positive and Negative Symptom Scale (PANSS) (rho=0.88, P=0.004). These results imply that [123I]epidepride, coupled with acute dopamine depletion might provide estimates of synaptic dopamine concentration.

Adult↗
PubMed2000

Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders.

Single photon emission computed tomography (SPECT) tracers selective for pre- and post-synaptic targets have allowed measurements of several aspects of dopaminergic (DA) neurotransmission. In this article, we will first review our DA transporter imaging in Parkinson's disease. We have developed the in vivo dopamine transporter (DAT) imaging with [123I]beta-CIT ((1R)-2beta-Carbomethoxy-3beta-(4-iodophenyl)tropane). This method showed that patients with Parkinson's disease have markedly reduced DAT levels in striatum, which correlated with disease severity and disease progression. Second, we applied DA imaging techniques in patients with schizophrenia. Using amphetamine as a releaser of DA, we observed the enhanced DA release, which was measured by imaging D2 receptors with [123I]IBZM (iodobenzamide), in schizophrenics. Further we developed the measurement of basal synaptic DA levels by AMPT (alpha-methyl-paratyrosine)-induced unmasking of D2 receptors. Finally, we expanded our techniques to the measurement of extrastriatal DA receptors using [123I]epidepride. The findings suggest that SPECT is a useful technique to measure DA transmission in human brain and may further our understanding of the pathophysiology of neuropsychiatric disorders.

Animals↗
PubMed2000

Behavioral changes and [123I]IBZM equilibrium SPECT measurement of amphetamine-induced dopamine release in rhesus monkeys exposed to subchronic amphetamine.

Previously we have shown that twelve weeks of repeated low-dose d-amphetamine (AMPH) exposure in rhesus monkeys induces a long-lasting enhancement of behavioral responses to acute low-dose challenge. The present study was designed to investigate the behavioral and neurochemical consequences of a six-week regimen of low-dose AMPH exposure (0.1-1.0 mg/kg, i.m., b.i.d.) in rhesus monkeys. SPECT imaging of AMPH's (0.4 mg/kg) ability to displace [123I]IBZM bound to D2 dopamine receptors in the striatum of saline control and AMPH-treated animals prior to and following chronic treatment was accomplished using a bolus/constant infusion paradigm. Following chronic AMPH treatment, all monkeys showed an enhanced behavioral response to acute AMPH challenge and a significant decrease in the percent of AMPH-induced displacement of [123I]IBZM in striatum compared to their pretreatment scans. These findings suggest that relatively small changes in presynaptic dopamine function may be reflected in significant alterations in the behavioral response to acute AMPH challenge.

Animals↗
PubMed2000

SPECT imaging with the D(4) receptor antagonist L-750,667 in nonhuman primate brain.

The suitability of an (123)I-labeled form of the putative D(4) receptor ligand L750,667 as a radiotracer for single photon emission computed tomography imaging was assessed in nonhuman primates. [(123)I]L750,667, labeled by iododestannylation, was administered to baboons in bolus and bolus plus constant infusion paradigms and imaged for 6 h. Total [(123)I]L750,667 brain uptake peaked (2.3% injected dose) at 15 min postinjection. [(123)I]L750,667 uptake was observed in all brain regions measured including diencephalon, brainstem, basal ganglia, cingulate cortex, and cerebellum, and slightly lower levels were noted in the frontal, parietal, temporoinsular, and occipital cortices. Administration of the D(4) receptor antagonist NGD 94-1 (2 mg/kg) did not displace radioactivity from any of the brain regions examined. Thus, while L750,667 is selective for the D(4) receptor in vitro, because brain [(123)I]L750,667 uptake was not displaced by NGD 94-1 at receptor saturating doses, [(123)I]L750,667 does not appear to be a suitable radiotracer for in vivo imaging of the D(4) receptor.

Animals↗
PubMed2000

Equilibrium modeling of 5-HT(2A) receptors with [18F]deuteroaltanserin and PET: feasibility of a constant infusion paradigm.

[(18)F]Altanserin has emerged as a promising positron emission tomography (PET) ligand for serotonin-2A (5-HT(2A)) receptors. The deuterium substitution of both of the 2'-hydrogens of altanserin ([(18)F]deuteroaltanserin) yields a metabolically more stable radiotracer with higher ratios of parent tracer to radiometabolites and increased specific brain uptake than [(18)F]altanserin. The slower metabolism of the deuterated analog might preclude the possibility of achieving stable plasma and brain activities with a bolus plus constant infusion within a reasonable time frame for an (18)F-labeled tracer (T(1/2) 110 min). Thus, the purpose of this study was to test the feasibility in human subjects of a constant infusion paradigm for equilibrium modeling of [(18)F]deuteroaltanserin with PET. Seven healthy male subjects were injected with [(18)F]deuteroaltanserin as a bolus plus constant infusion lasting 10 h postinjection. PET acquisitions and venous blood sampling were performed throughout the infusion period. Linear regression analysis revealed that time-activity curves for both specific brain uptake and plasma [(18)F]deuteroaltanserin concentration stabilized after about 5 h. This permitted equilibrium modeling and estimation of V(')(3) (ratio of specific uptake to total plasma parent concentration) and the binding potential V(3) (ratio of specific uptake to free plasma parent concentration). Cortical/cerebellar ratios were increased by 26% relative to those we previously observed with [(18)F]altanserin using similar methodology in a somewhat older subject sample. These results demonstrate feasibility of equilibrium imaging with [(18)F]deuteroaltanserin and suggest that it may be superior to [(18)F]altanserin as a PET radioligand.

Adolescent↗
PubMed2000

[123I]IPCIT and [123I]beta-CIT as SPECT tracers for the dopamine transporter: a comparative analysis in nonhuman primates.

[123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]-CIT) and its isopropylester analog [123I]PCIT, both of which are phenyltropane derivatives of cocaine with high affinity for the dopamine (DA) transporter, were compared using single photon emission computed tomography in nonhuman primates. Although IPCIT is significantly more selective for the DA transporter than beta-CIT, striatal distribution volumes of specifically bound tracer were similar for both tracers. Compartmental modeling results were compared with a simple peak equilibrium method used previously by this group. The peak equilibrium method is shown to overestimate striatal distribution volumes, primarily due to a difference in the calculated time of peak specific uptake.

Animals↗
PubMed2000

5-Iodo-A-85380, an alpha4beta2 subtype-selective ligand for nicotinic acetylcholine receptors.

In an effort to develop selective radioligands for in vivo imaging of neuronal nicotinic acetylcholine receptors (nAChRs), we synthesized 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380) and labeled it with (125)I and (123)I. Here we present the results of experiments characterizing this radioiodinated ligand in vitro. The affinity of 5-[(125)I]iodo-A-85380 for alpha4beta2 nAChRs in rat and human brain is defined by K(d) values of 10 and 12 pM, respectively, similar to that of epibatidine (8 pM). In contrast to epibatidine, however, 5-iodo-A-85380 is more selective in binding to the alpha4beta2 subtype than to other nAChR subtypes. In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing alpha3 and beta4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinity of epibatidine at alpha7 and muscle-type nAChRs, respectively. Moreover, unlike epibatidine and cytisine, 5-[(125)I]iodo-A-85380 shows no binding in any brain regions in mice homozygous for a mutation in the beta2 subunit of nAChRs. Binding of 5-[(125)I]iodo-A-85380 in rat brain is reversible, and is characterized by high specificity and a slow rate of dissociation of the receptor-ligand complex (t(1/2) for dissociation approximately 2 h). These properties, along with other features observed previously in in vivo experiments (low toxicity, rapid penetration of the blood-brain barrier, and a high ratio of specific to nonspecific binding), suggest that this compound, labeled with (125)I or (123)I, is superior to other radioligands available for in vitro and in vivo studies of alpha4beta2 nAChRs, respectively.

Animals↗