Biomedical subjects

Alane S Kimes

Publications and source records attributed to Alane S Kimes.

14 recordsLinked to original sources

PubMed2006

Increased occupancy of dopamine receptors in human striatum during cue-elicited cocaine craving.

In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [(11)C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.

Adult↗

PubMed2005

In vitro characterization of 6-[18F]fluoro-A-85380, a high-affinity ligand for alpha4beta2* nicotinic acetylcholine receptors.

Nicotinic acetylcholine receptors are involved in tobacco dependence and several other neuropathologies (e.g., Alzheimer's disease, Parkinson's disease), as well as in attention, learning, and memory. Performing in vivo imaging of these receptors in humans holds great promise for understanding their role in these conditions. Recently, three radiohalogenated analogs of 3-(2(S)-azetidinylmethoxy)pyridine (A- 85380) were used successfully for the in vivo visualization of alpha4beta2* nicotinic receptors in the human brain with PET/SPECT. Herein, we present the results of the in vitro characterization of one of these radioligands, 6-[18F]fluoro-3-(2(S)-azetidinylmethoxy)-pyridine (6-[18F]fluoro-A-85380), which is a fluoro-analog of the potent nonopioid analgesic ABT-594. In human postmortem cortical tissue, 6-[18F]fluoro-A-85380 reversibly binds with high affinity to a single population of sites (Kd = 59 pM at 37 degrees C, Bmax = 0.7 pmol/g tissue). The binding is fully reversible and is characterized at 37 degrees C by T(1/2assoc) = 2.2 min (at a ligand concentration of 39 pM) and by T(1/2dissoc) = 3.6 min. 6-Fluoro-A-85380 exhibits clear selectivity for alpha4beta2* over the other major mammalian nicotinic receptor subtypes: alpha7, alpha3beta4, and muscle-type. These results suggest that 6-[18F]fluoro-A-85380 is a promising radioligand for in vivo imaging of brain alpha4beta2* nicotinic receptors.

Animals↗

PubMed2005

Risky decision making and the anterior cingulate cortex in abstinent drug abusers and nonusers.

Risky decision making is a hallmark behavioral phenotype of drug abuse; thus, an understanding of its biological bases may inform efforts to develop therapies for addictive disorders. A neurocognitive task that measures this function (Rogers Decision-Making Task; RDMT) was paired with measures of regional cerebral perfusion to identify brain regions that may underlie deficits in risky decision making in drug abusers. Subjects were abstinent drug abusers (> or =3 months) and healthy controls who underwent positron emission tomography scans with H(2)(15)O. Drug abusers showed greater risk taking and heightened sensitivity to rewards than control subjects. Both drug abusers and controls exhibited significant activations in a widespread network of brain regions, primarily in the frontal cortex, previously implicated in decision-making tasks. The only significant group difference in brain activation, however, was found in the left pregenual anterior cingulate cortex, with drug abusers exhibiting less task-related activation than control subjects. There were no significant correlations between neural activity and task performance within the control group. In the drug abuse group, on the other hand, increased risky choices on the RDMT negatively correlated with activation in the right hippocampus, left anterior cingulate gyrus, left medial orbitofrontal cortex, and left parietal lobule, and positively correlated with activation in the right insula. Drug abuse severity was related positively to right medial orbitofrontal activity. Attenuated activation of the pregenual ACC in the drug abusers relative to the controls during performance on the RDMT may underlie the abusers' tendency to choose risky outcomes.

Adult↗

PubMed2004

Pharmacological and toxicological evaluation of 2-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-F-A-85380), a ligand for imaging cerebral nicotinic acetylcholine receptors with positron emission tomography.

2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(18)F]F-A-85380), a positron emission tomography (PET) radioligand for neuronal alpha4beta2(*) nicotinic acetylcholine receptors, was evaluated for its pharmacology and safety. In the Ames test for mutagenicity, 2-F-A-85380 was without effect in five bacterial strains. No evidence of gross pathology or histopathological changes occurred in either 2-day acute (0.4-4000 nmol/kg i.v.) or 14-day expanded acute (40-4000 nmol/kg i.v.) toxicity studies in mice. Similarly, hematology and serum chemistry values in rhesus monkeys administered 60 nmol/kg i.v. were not affected over 14 days. Like nicotine, 2-F-A-85380 produced convulsions in mice at very high doses. The ED(50) value of 2-F-A-85380 for eliciting tonic-clonic convulsions (5.0 micromol/kg i.v.) was nearly 4 times greater than that of nicotine (ED(50) = 1.4 micromol/kg i.v.). Lower doses of 2-F-A-85380 (30-300 nmol/kg i.v.) and nicotine (20-400 nmol/kg i.v.) increased systolic and diastolic blood pressure, heart rate, and cardiac contractility in rats. Notably, the PR, QRS, or QTc intervals of the rat electrocardiogram were unaffected by either drug. Dosimetry studies indicated that the urinary bladder wall was the critical organ and total radiation exposure was within acceptable limits. Estimated doses of 2-F-A-85380 required to elevate blood pressure and heart rate by 10% ranged from 40 to 58 nmol/kg i.v. Nevertheless, the estimated radiopharmaceutically relevant dose of [(18)F]2-F-A-8380 required for initial PET imaging studies, 10 pmol/kg, is less than 1/4000th of the doses calculated (40-58 nmol/kg i.v.) to elevate blood pressure and heart rate by 10% in humans and should elicit no clinically significant effects and have acceptable dosimetry.

Animals↗

PubMed2004

5-substituted derivatives of 6-halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with low picomolar affinity for alpha4beta2 nicotinic acetylcholine receptor and wide range of lipophilicity: potential probes for imaging with positron emission tomography.

Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (log D) ranging from -1.6 to +1.5 have been synthesized. Most members of the series, which are derivatives of 5-substituted-6-halogeno-A-85380, exhibited a higher binding affinity at alpha4beta2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role of the orientation of the additional heterocyclic ring on the binding affinity of the ligands with nAChRs. The existing nicotinic pharmacophore models do not accommodate this finding. Two compounds of the series, 6-[(18)F]fluoro-5-(pyridin-3-yl)-A-85380 ([(18)F]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-[(18)F]fluoropyridin-5-yl)pyridine) ([(18)F]35), were radiolabeled with (18)F. Comparison of PET data for [(18)F]31 and 2-[(18)F]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [(18)F]35 demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[(18)F]FA. Therefore, [(18)F]35 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs.

Animals↗

PubMed2004

Evaluation of 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine and its analogues as PET radioligands for imaging nicotinic acetylcholine receptors.

A novel series of compounds derived from the high-affinity nicotinic acetylcholine receptor (nAChR) ligand, 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine (Me-p-PVC), originally developed by Abbott Laboratories, was characterized in vitro in nAChR binding assays at 37 degrees C to show K(i) values in the range of 9-611 pm. Several compounds of this series were radiolabeled with (11)C and evaluated in vivo in mice and monkeys as potential candidates for PET imaging of nAChRs. [(11)C]Me-p-PVC (K(i) =56 pm at 37 degrees C; logD = 1.6) was identified as a radioligand suitable for the in vivo imaging of the alpha 4 beta 2* nAChR subtype. Compared with 2-[(18)F]FA, a PET radioligand that has been successfully used in humans and is characterized by a slow kinetic of brain distribution, [(11)C]Me-p-PVC is more lipophilic. As a result, [(11)C]Me-p-PVC accumulated in the brain more rapidly than 2-[(18)F]FA. Pharmacological evaluation of Me-p-PVC in mice demonstrated that the toxicity of this compound was comparable with or lower than that of 2-FA. Taken together, these results suggest that [(11)C]Me-p-PVC is a promising PET radioligand for studying nAChR occupancy by endogenous and exogenous ligands in the brain in vivo.

Animals↗

PubMed2003

Quantification of nicotinic acetylcholine receptors in human brain using [123I]5-I-A-85380 SPET.

The purpose of this study was to assess the utility of a new single-photon emission tomography ligand, [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), to measure regional nAChR binding in human brain. Six healthy nonsmoker subjects (two men and four women, age 33 +/- 15 years) participated in both a bolus (dose: 317 +/- 42 MBq) and a bolus plus constant infusion (dose of bolus: 98 +/- 32 MBq, B/I=6.7 +/- 2.6 h, total dose: 331 +/- 55 MBq) study. The study duration was 5-8 h and 14 h in the former and the latter, respectively. Nonlinear least-squares compartmental analysis was applied to bolus studies to calculate total (VT') and specific (VS') distribution volumes. A two-tissue compartment model was applied to identify VS'. VT' was also calculated in B/I studies. In bolus studies, VT' was well identified by both one- and two-tissue compartment models, with a coefficient of variation of less than 5% in most regions. The two-compartment model gave VT' values of 51, 22, 27, 32, 20, 19, 20, and 17 ml cm(-3) in thalamus, cerebellum, putamen, pons, and frontal, parietal, temporal, and occipital cortices, respectively. The two-compartment model did not identify VS' well. B/I studies provided poor accuracy of VT' measurement, possibly due to deviations from equilibrium conditions. These results demonstrate the feasibility of quantifying high-affinity type nAChRs using [123I]5-I-A-85380 in humans and support the use of VT' measured by bolus studies.

Adult↗

PubMed2003

2-[18F]F-A-85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans.

Noninvasive imaging of nicotinic acetylcholine receptors (nAChRs) in the human brain in vivo is critical for elucidating the role of these receptors in normal brain function and in the pathogenesis of brain disorders. Here we report the first in vivo visualization of human brain areas containing nAChRs by using PET and 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2-[18F]FA). We acquired scans from six healthy non-smoking volunteers after i.v. bolus administration of 2-[18F]FA (1.6 MBq/kg or 0.043 +/- 0.002 mCi/kg). This dose was sufficient for visualizing nAChRs in the thalamus up to 5 h after injection. There were no adverse effects associated with administration of no-carrier-added 2-[18F]FA (1.3-10 pmol/kg). Consistent with the distribution of nAChRs in human brain, accumulated radioactivity was greatest in thalamus, intermediate in the midbrain, pons, cerebellum, and cortex; and least in white matter. As approximately 90% of the injected radioactivity was eliminated via the urine (biological half-life ca. 4 h), the urinary bladder wall received the highest radiation dose. The estimate of radiation dose equivalent to the urinary bladder wall (ca. 180 +/- 30 mSv/MBq or 0.7 rem/mCi with a 2.4 h void interval) suggests that multiple studies could be performed in a single subject. The results predict that quantitative PET imaging of nAChRs in human brain with 2-[18F]FA is feasible.

Azetidines↗

PubMed2003

Graphical analysis of 2-[18F]FA binding to nicotinic acetylcholine receptors in rhesus monkey brain.

External imaging of nicotinic acetylcholine receptors (nAChRs) using techniques such as PET would help to clarify the roles of these receptors in the physiology and pathology of brain function. Here we report the results of quantitative PET studies of cerebral nAChRs with 2-[(18)F]fluoro-A-85380 (2-[(18)F]FA) in rhesus monkeys. Data from dynamic PET scans were analyzed using graphical methods. Binding potential (BP) values of 2.0, 0.4, 0.3, and 0.03 observed in the thalamus (Th), cortex (Cx), striatum (Str), and cerebellum (Cb), respectively, were consistent with the pattern of alpha(4)beta(2) nAChR distribution in monkey brain. The high value of 2-[(18)F]FA-specific binding in the rhesus monkey Th and low level of that in Cb compared with nonspecific accumulation of radioactivity in these structures allowed use of Cb as a reference region for calculation of BP and volume of distribution of specific binding (VDsb) in Th by graphical methods, both with and without the plasma input function. In contrast, estimation of 2-[(18)F]FA specific binding in low-receptor-density regions such as Cx and Str required assessment of nondisplaceable volume of distribution (VDnd) in a separate study and measurement of nonmetabolized radioligand concentrations in the plasma. For accurate quantitation of 2-[(18)F]FA-specific binding by graphical analysis, PET studies should last up to 7 h due to the slow kinetics of 2-[(18)F]FA brain distribution. Further, to avoid substantial underestimation in measured BP values the doses of administered 2-[(18)F]FA should not exceed 0.1 nmol/kg body weight. The findings suggest that 2-[(18)F]FA is a promising ligand for quantitation of nAChRs in human brain.

Animals↗

PubMed2003

Neuroimaging and mechanisms of drug abuse: interface of molecular imaging and molecular genetics.

Whereas ligand studies can inform the end-products of dysregulation of genetic expression, reporter gene imaging can provide the means to understand the genetic origin of these end-products. As with radioligand studies, in vivo direct measurement of gene expression will allow genetic processes to be monitored over time in the same subject, use of a subject as his/her own control in intervention studies (i.e., measurement before and after an intervention), and monitoring the spatial distribution of molecular events in the whole brain. Furthermore, reporter gene imaging, by advancing knowledge of the biologic mechanisms of disease states, has important clinical implications, particularly in the development and monitoring of treatments. We expect PET to play a prominent role in the elucidation of substance abuse mechanisms and contribute significantly to the development of innovative treatment strategies.

Brain↗

PubMed2003

Decision making in adolescents with behavior disorders and adults with substance abuse.

OBJECTIVE: The study assessed the validity of the Gambling Task as a test of decision-making ability in adolescents and examined whether adolescents with behavior disorders, who are at risk for substance abuse, have deficits in decision making similar to those exhibited by adults with substance abuse. METHOD: Performance on the Gambling Task in two testing sessions separated by 1 week was assessed in 64 12-14-year-old adolescents (31 healthy, 33 with externalizing behavior disorders) and 52 adults (22 healthy, 30 with substance abuse). RESULTS: The healthy adolescents and the healthy adults had similar performance on the Gambling Task. Adolescents with behavior disorders performed more poorly than healthy adolescents, but only in the second testing session. In adults, overall Gambling Task performance did not differ between the healthy and substance abuse groups at either testing session, indicating no difference in learning of decision-making strategies between groups. However, adults with substance abuse performed more poorly than healthy adults during an early stage of the task, when participants presumably begin to understand the rewards and penalties involved in the task but are not yet sure of the actual risk of incurring penalities. CONCLUSIONS: The Gambling Task can be used with adolescents. Testing with the Gambling Task revealed a deficit in decision making in adolescents with behavior disorders, who are at risk for substance abuse. This deficit may represent a vulnerability factor for the development of substance abuse.

Adolescent↗

PubMed2003

Neural substrates of decision making in adults with attention deficit hyperactivity disorder.

OBJECTIVE: The characteristics of attention deficit hyperactivity disorder (ADHD) include abnormalities in reward responsivity that may interfere with decision making. The study examined reward responsivity in ADHD by comparing the neural correlates of decision making in adults with childhood-onset ADHD and in healthy adults. METHOD: The neural correlates of performance on a decision-making task and a control task were compared in 10 adults with ADHD and 12 age-matched healthy volunteers by using [(15)O]H(2)O positron emission tomography. The decision-making task tested the ability to weigh short-term rewards against long-term losses. The control task matched all components of the decision-making task except for the decision-making process and related contingency. RESULTS: The ventral and dorsolateral prefrontal cortex and the insula were activated during performance of the decision-making task in both the ADHD and healthy groups; however, activation in the ADHD group was less extended and did not involve other regions, such as anterior cingulate and hippocampus, that subserve emotion/memory processes. Direct comparison of data from the ADHD subjects and the healthy volunteers suggested that the healthy subjects engaged the hippocampal and insular regions more than did the ADHD subjects and that the ADHD subjects recruited the caudal part of the right anterior cingulate more than did the healthy subjects. CONCLUSIONS: The findings suggest that the neural circuits engaged during decision making differ in subjects with ADHD and healthy comparison subjects. This difference may explain observed deficits in motivated behaviors in ADHD. A better understanding of the nature of these deficits could ultimately be applied to refine treatment strategies for ADHD.

Adult↗

PubMed2002

Whole-body biodistribution, radiation absorbed dose, and brain SPET imaging with [123i]5-i-A-85380 in healthy human subjects.

The biodistribution of radioactivity after the administration of a new tracer for alpha4beta2 nicotinic acetylcholine receptors (nAChRs), [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), was studied in ten healthy human subjects. Following administration of 98+/-6 MBq [123I]5-I-A-85380, serial whole-body images were acquired over 24 h and corrected for attenuation. One to four brain single-photon emission tomography (SPET) images were also acquired between 2.5 and 24 h. Estimates of radiation absorbed dose were calculated using MIRDOSE 3.1 with a dynamic bladder model and a dynamic gastrointestinal tract model. The estimates of the highest absorbed dose (microGy/MBq) were for the urinary bladder wall (71 and 140), lower large intestine wall (70 and 72), and upper large intestine wall (63 and 64), with 2.4-h and 4.8-h urine voiding intervals, respectively. The whole brain activity at the time of the initial whole-body imaging at 14 min was 5.0% of the injected dose. Consistent with the known distribution of alpha4beta2 nAChRs, SPET images showed the highest activity in the thalamus. These results suggest that [123I]5-I-A-85380 is a promising SPET agent to image alpha4beta2 nAChRs in humans, with acceptable dosimetry and high brain uptake.

Adult↗

PubMed2002

Decision-making in a risk-taking task: a PET study.

As decision-making is central to motivated behavior, understanding its neural substrates can help elucidate the deficits that characterize various maladaptive behaviors. Twenty healthy adults performed a risk-taking task during positron emission tomography with (15)O-labeled water. The task, a computerized card game, tests the ability to weigh short-term rewards against long-term losses. A control task matched all components of the risk-taking task except for decision-making and the difference between responses to contingent and non-contingent reward and punishment. Decision-making (2 runs of the active task minus 2 runs of the control task) activated orbital and dorsolateral prefrontal cortex, anterior cingulate, insula, inferior parietal cortex and thalamus predominantly on the right side, and cerebellum predominantly on the left side. In an exploratory analysis, guessing (run 1 minus run 2 of the active task) accompanied activation of sensory-motor associative areas, and amygdala on the left side, whereas informed decision-making (run 2 minus run 1) activated areas that subserve memory (hippocampus, posterior cingulate) and motor control (striatum, cerebellum). The findings provide a framework for future investigations of decision-making in maladaptive behaviors.

Adult↗