Striatal and Extrastriatal Monoaminergic Disruption in Progressive Supranuclear Palsy.

BACKGROUND: As a biomarker targeting vesicular monoamine transporter 2 (VMAT2), 18F-9-fluoropropyldihydrotetrabenazine (18F-FP-DTBZ) positron emission tomography (PET) is highly accurate in diagnosing Parkinson's disease (PD) and assessing its severity. However, evidence is insufficient in patients with progressive supranuclear palsy (PSP). OBJECTIVE: We evaluated the striatal and extrastriatal monoaminergic disruption of PSP and differences in patterns between patients with PSP, PD, and healthy controls (HCs) using 18F-FP-DTBZ PET, as well as its correlations with the clinical characteristics of PSP. METHODS: We recruited 58 patients with PSP, 23 age- and duration-matched patients with PD, as well as 17 HCs. Patients were scanned using 18F-FP-DTBZ PET/computed tomography, and images were spatially normalized and analyzed based on the volume of interest. RESULTS: VMAT2 binding differed significantly in the striatum and substantia nigra among the groups (P < 0.001). A more severe disruption in the caudate was noted in the PSP group (P < 0.001) than in the PD group. However, no differences were found in the nucleus accumbens, hippocampus, amygdala, or raphe between the PD and PSP groups. Within the PSP group, striatal VMAT2 binding was significantly associated with the fall/postural stability subscore of the PSP Rating Scale, especially in the putamen. Furthermore, VMAT2 binding was correlated with Mini-Mental State Examination or Montreal Cognitive Assessment in the hippocampus. CONCLUSIONS: Caudate disruptions showed prominent differences among the groups. VAMT2 binding in the striatum and hippocampus reflects the severity of fall/postural stability and cognition, respectively. © 2024 International Parkinson and Movement Disorder Society.

Brain microglia activation and peripheral adaptive immunity in Parkinson's disease: a multimodal PET study.

BACKGROUND: Abnormal activation of immune system is an important pathogenesis of Parkinson's disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear. OBJECTIVES: To evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity. METHODS: In this case-control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson's disease. 18F-PBR06 PET/MR for microglia activation, 18F-FP-DTBZ for dopaminergic denervation, total account of T cells and subpopulations of T helper (Th1/Th2/Th17) cells, and the levels of serum inflammatory cytokines were assessed. Sanger sequencing was used to exclude the mix-affinity binders of 18F-PBR06-PET. RESULTS: Compared to healthy controls, patients with Parkinson's disease had an increased 18F-PBR06-PET standardized uptake value ratio (SUVR) in the putamen, particularly in the ipsilateral side of the motor onset. 18F-PBR06-PET SUVR was positively associated with 18F-FP-DTBZ-PET SUVR in the brainstem and not associated with disease severity measured by Hoehn and Yahr stage, MDS-UPDRS III scores. Patients with Parkinson's disease had elevated frequencies of Th1 cells and serum levels of IL10 and IL17A as compared to healthy controls. No significant association between peripheral inflammation markers and microglia activation in the brain of PD was observed. CONCLUSION: Parkinson's disease is associated with early putaminal microglial activation and peripheral phenotypic Th1 bias. Peripheral adaptive immunity might be involved in microglia activation in the process of neurodegeneration in PD indirectly, which may be a potential biomarker for the early detection and the target for immunomodulating therapy.

Identification and in vivo evaluation of a fluorine-18 rolipram analogue, [(18) F]MNI-617, as a radioligand for PDE4 imaging in mammalian brain.

Phosphodiesterase (PDE) 4 is the most prevalent PDE in the central nervous system (CNS) and catalyzes hydrolysis of intracellular cAMP, a secondary messenger. By therapeutic inhibition of PDE4, intracellular cAMP levels can be stabilized, and the symptoms of psychiatric and neurodegenerative disorders including depression, memory loss and Parkinson's disease can be ameliorated. Radiotracers targeting PDE4 can be used to study PDE4 density and function, and evaluate new PDE4 therapeutics, in vivo in a non-invasive way, as has been shown using the carbon-11 labeled PDE4 inhibitor R-(-)-rolipram. Herein we describe a small series of rolipram analogs that contain fluoro- or iodo-substituents that could be used as fluorine-18 PET or iodine-123 SPECT PDE4 radiotracers. This series was evaluated with an in vitro binding assay and a 4-(fluoromethyl) derivative of rolipram, MNI-617, was identified, with a five-fold increase in affinity for PDE4 (Kd = 0.26 nM) over R-(-)-rolipram (Kd = 1.6 nM). A deutero-analogue d2 -[(18) F]MNI-617 was radiolabeled and produced in 23% yield with high (>5 Ci/µmol) specific activity and evaluated in non-human primate, where it rapidly entered the brain, with SUVs between 4 and 5, and with a distribution pattern consistent with that of PDE4.

18F-FP-DTBZ PET/CT detectable associations between monoaminergic depletion in the putamen with rigidity and the pallidus with tremor in Parkinson's disease.

INTRODUCTION: The motor subtypes of Parkinson's disease (PD) are widely accepted and implemented. However, the motor subtypes have been thought to represent different stages of PD recently because some patients experience tremor-dominant (TD) conversion to the non-tremor-dominant subtype, such as postural instability-gait difficulty (PIGD). In this study, we explore the monoaminergic denervation features of the striatal and extra-striatal areas in patients with different subtypes of PD with 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-FP-DTBZ) PET/CT. METHODS: Sixty-five patients diagnosed with PD were included and classified as TD (n = 25) and PIGD (n = 40). We evaluated the difference of monoaminergic features of each subregion of brain between motor subtypes of PD, as well as associations between these features and Parkinsonian motor symptoms. RESULTS: The striatal standardized uptake value ratios (SUVR) showed that dopaminergic disruption of patients with PIGD was more symmetrical in the posterior ventral putamen (p < 0.001) and more severe in the ipsilateral posterior dorsal putamen (p < 0.001 corrected) compared with that of patients with TD. The severity of PIGD scores was associated with striatal dopaminergic depletion, while tremor was associated with monoaminergic changes in extra-striatal areas, including pallidus, thalamus, and raphe nuclie. CONCLUSION: These results indicate that patients with different motor subtypes may have different underlying mechanisms of PD pathogenesis. Therefore, accurate diagnosis of PD subtypes can aid prognosis evaluation and treatment decision-making.

Synthesis and biological evaluation of positron emission tomography radiotracers targeting serotonin 4 receptors in brain: [18F]MNI-698 and [18F]MNI-699.

Two new benzodioxane derivatives were synthesized as candidates to image the serotonin 4 receptors by positron emission tomography (PET) and radiolabeled with fluorine-18 via a two-step procedure. Competition binding assays demonstrated that MNI-698 and MNI-699 had sub-nanomolar binding affinities against rat striatal 5-HT4 receptors (Ki of 0.20 and 0.07 nM, respectively). PET imaging in rhesus monkey showed that the regional brain distribution of [(18)F]MNI-698 and [(18)F]MNI-699 were consistent with the known densities of 5-HT4 in brain. [(18)F]MNI-698 and [(18)F]MNI-699 are among the first fluorine-18 radiotracers developed for imaging the 5-HT4 receptors in vivo and are currently under preclinical investigation in primates for future human use.

Diagnostic value of striatal 18F-FP-DTBZ PET in Parkinson's disease.

Background: 18F-FP-DTBZ has been proven as a biomarker for quantifying the concentration of presynaptic vesicular monoamine transporter 2 (VMAT2). However, its clinical application is still limited. Objectives: To evaluate the difference in dopaminergic integrity between patients with Parkinson's disease (PD) and healthy controls (HC) using 18F-FP-DTBZ PET in vivo and to determine the diagnostic value of standardized uptake value ratios (SUVRs) using the Receiver Operating Characteristic (ROC) curve. Methods: A total of 34 PD and 31 HC participants were enrolled in the PET/MR derivation cohort, while 89 PD and 18 HC participants were recruited in the PET/CT validation cohort. The Hoehn-Yahr Scale and the third part of the MDS-Unified Parkinson's Disease Rating Scale (MDSUPDRS-III) were used to evaluate the disease staging and severity. All assessments and PET scanning were performed in drug-off states. The striatum was segmented into five subregions as follows: caudate, anterior dorsal putamen (ADP), anterior ventral putamen (AVP), posterior dorsal putamen (PDP), and posterior ventral putamen (PVP) using automatic pipeline built with the PMOD software (version 4.105). The SUVRs of the targeted subregions were calculated using the bilateral occipital cortex as the reference region. Results: Regarding the diagnostic value, ROC curve and blind validation showed that the contralateral PDP (SUVR = 3.43) had the best diagnostic accuracy (AUC = 0.973; P < 0.05), with a sensitivity of 97.1% (95% CI: 82.9-99.8%), specificity of 100% (95% CI: 86.3-100%), positive predictive value (PPV) of 100% (95% CI: 87.0-100%), negative predictive value (NPV) of 96.9% (95% CI: 82.0-99.8%), and an accuracy of 98.5% for the diagnosis of PD in the derivation cohort. Blind validation of 18F-FP-DTBZ PET imaging diagnosis was done using the PET/CT cohort, where participants with a SUVR of the PDP <3.43 were defined as PD. Kappa test showed a consistency of 0.933 (P < 0.05) between clinical diagnosis and imaging diagnosis, with a sensitivity of 98.9% (95% CI: 93.0-99.9%), specificity of 94.4% (95% CI: 70.6-99.7%), PPV of 98.9% (95% CI: 93.0-99.9%), NPV of 94.4% (95% CI: 70.6-99.7%), and a diagnostic accuracy of 98.1%. Conclusions: Our results showed that an SUVR threshold of 3.43 in the PDP could effectively distinguish patients with PD from HC.

Corrigendum: Diagnostic value of striatal 18F-FP-DTBZ PET in Parkinson's disease.

[This corrects the article DOI: 10.3389/fnagi.2022.931015.].

2-Arylimidazo[2,1-b]benzothiazoles: a new family of amyloid binding agents with potential for PET and SPECT imaging of Alzheimer's brain.

We designed and synthesized a small series of 2-aryl-imidazo[2,1-b]benzothiazole, representing a combination of motifs from the two most potent amyloid imaging agents, PIB and IMPY. The binding affinity of the new compounds ranged from 6 to 133 nM. Among the best compounds, 3b (K(i)=6 nM) can be labeled with (11)CH(3) for PET imaging whereas 3j (K(i)=10.9 nM) can be labeled with (123)I for SPECT imaging.

Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series.

We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.

Beta2* nicotinic acetylcholine receptors modulate pain sensitivity in acutely abstinent tobacco smokers.

INTRODUCTION: Nicotine and tobacco smoking administration have demonstrated antinociceptive effects that are mediated by the nicotinic acetylcholine receptor containing the beta2* subunit (beta(2)*-nAChR). In this study, we examined the relationship between beta(2)*-nAChR availability and nociception during acute withdrawal in human tobacco smokers using [(123)I]5-IA-85380 ([(123)I]5-IA) and single photon emission computed tomography (SPECT) brain imaging. METHODS: Tobacco smokers (n = 24, aged 34 +/- 11 years) participated in the cold pressor task during acute withdrawal (up to 3 hr) and a second cold pressor task following 7-13 days of smoking abstinence on the day they were imaged with [(123)I]5-IA SPECT. The cold pressor task is used to measure pain sensitivity (when subjects first feel pain) and pain tolerance (when subjects cannot withstand pain). RESULTS: Following 7-13 days of tobacco smoking abstinence, increased pain sensitivity, for example, shorter time to first feel pain, was significantly associated with higher beta(2)*-nAChR availability in the thalamus (r = -.43), parietal (r = -.50), frontal (r = -.55), anterior cingulate (r = -.44), temporal (r = -.43), and occipital (r = -.48) cortices. The percent change in pain sensitivity from the first to second cold pressor task was significantly correlated with beta(2)*-nAChR availability in the thalamus (r = -.57), cerebellum (r = -.50), striatum (r = -.057), parietal (r = -.46), anterior cingulate (r = -.48), temporal (r = -.55), and occipital (r = -.57) cortices. Similar associations were not observed with pain tolerance. DISCUSSION: This suggests that beta(2)*-nAChRs play a role in pain sensitivity but not pain tolerance during tobacco smoking withdrawal. If individuals are more likely to relapse in response to painful stimuli, lower beta(2)*-nAChR availability during acute abstinence may be protective.

Rapidly (and Successfully) Translating Novel Brain Radiotracers From Animal Research Into Clinical Use.

The advent of preclinical research scanners for in vivo imaging of small animals has added confidence into the multi-step decision-making process of radiotracer discovery and development. Furthermore, it has expanded the utility of imaging techniques available to dissect clinical questions, fostering a cyclic interaction between the clinical and the preclinical worlds. Significant efforts from medicinal chemistry have also made available several high-affinity and selective compounds amenable for radiolabeling, that target different receptors, transporters and enzymes in vivo. This substantially increased the range of applications of molecular imaging using positron emission tomography (PET) or single photon emission computed tomography (SPECT). However, the process of developing novel radiotracers for in vivo imaging of the human brain is a multi-step process that has several inherent pitfalls and technical difficulties, which often hampers the successful translation of novel imaging agents from preclinical research into clinical use. In this paper, the process of radiotracer development and its relevance in brain research is discussed; as well as, its pitfalls, technical challenges and future promises. Examples of successful and unsuccessful translation of brain radiotracers will be presented.

123I-5-IA-85380 SPECT imaging of nicotinic receptors in Alzheimer disease and mild cognitive impairment.

UNLABELLED: Postmortem binding studies have established that the concentration of alpha(4)beta(2)-nicotinic acetylcholine receptors (alpha(4)beta(2)-nAChR) is reduced in advanced Alzheimer disease (AD). However, the status of this receptor in mild or prodromal AD has remained the subject of controversy. METHODS: We compared alpha(4)beta(2)-nAChR availability in 8 brain regions of living human subjects who had AD and mild cognitive impairment (MCI) with that in age-matched healthy control subjects by using the ligand (123)I-5-IA-85380 ((123)I-5-IA) and SPECT. All subjects (n = 32) were nonsmokers; they were administered (123)I-5-IA as a bolus plus a constant infusion and imaged 6-8 h later under equilibrium conditions. The effect of diagnosis on regional alpha(4)beta(2)-nAChR availability (regional brain activity/total parent concentration in plasma, proportional to the binding potential) was analyzed using multivariate analysis of covariance, controlling for the effects of age and sex. RESULTS: Despite a significant overall effect of diagnostic group on mean alpha(4)beta(2)-nAChR availability, univariate analyses revealed no group differences for any brain region analyzed. An exploratory analysis of the relationship between regional alpha(4)beta(2)-nAChR availability and neuropsychologic variables yielded several plausible correlations. However, after Bonferroni adjustment, only the correlation between the anterior cingulate and the Trail Making Test, Part B, in the healthy control subjects remained significant. CONCLUSION: These results are consistent with several postmortem and in vivo studies suggesting the preservation of nAChRs during the prodromal and early stages of AD. They support the interpretation that nAChR and other cholinergic reductions in AD are late-stage phenomena.

GABAA-benzodiazepine receptor availability in smokers and nonsmokers: relationship to subsyndromal anxiety and depression.

Many smokers experience subsyndromal anxiety symptoms while smoking and during acute abstinence, which may contribute to relapse. We hypothesized that cortical gamma aminobutyric acid(A)-benzodiazepine receptor (GABA(A)-BZR) availability in smokers and nonsmokers might be related to the expression of subsyndromal anxiety, depressive, and pain symptoms. Cortical GABA(A)-BZRs were imaged in 15 smokers (8 men and 7 women), and 15 healthy age and sex-matched nonsmokers, and 4 abstinent tobacco smokers (3 men; 1 woman) using [(123)I]iomazenil and single photon emission computed tomography (SPECT). Anxiety and depressive symptoms were measured using the Spielberger's State-Trait Anxiety Index (STAI) and the Center for Epidemiology Scale for Depressive Symptoms (CES-D). The cold pressor task was administered to assess pain tolerance and sensitivity. The relationship between cortical GABA(A)-BZR availability, smoking status, and subsyndromal depression and anxiety symptoms, as well as pain tolerance and sensitivity, were evaluated. Surprisingly, there were no statistically significant differences in overall GABA(A)-BZR availability between smokers and nonsmokers or between active and abstinent smokers; however, cortical GABA(A)-BZR availability negatively correlated with subsyndromal state anxiety symptoms in nonsmokers but not in smokers. In nonsmokers, the correlation was seen across many brain areas with state anxiety [parietal (r = -0.47, P = 0.03), frontal (r = -0.46, P = 0.03), anterior cingulate (r = -0.47, P = 0.04), temporal (r = -0.47, P = 0.03), occipital (r = -0.43, P = 0.05) cortices, and cerebellum (r = -0.46, P = 0.04)], trait anxiety [parietal (r = -0.72, P = 0.02), frontal (r = -0.72, P = 0.02), and occipital (r = -0.65, P = 0.04) cortices] and depressive symptoms [parietal (r = -0.68; P = 0.02), frontal (r = -0.65; P = 0.03), anterior cingulate (r = -0.61; P = 0.04), and temporal (r = -0.66; P = 0.02) cortices]. The finding that a similar relationship between GABA(A)-BZR availability and anxiety symptoms was not observed in smokers suggests that there is a difference in GABA(A)-BZR function, but not number, in smokers. Thus, while subsyndromal anxiety and depressive symptoms in nonsmokers may be determined in part by GABA(A)-BZR availability, smoking disrupts this relationship. Aberrant regulation of GABA(A)-BZR function in vulnerable smokers may explain why some smokers experience subsyndromal anxiety and depression.

Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque.

A series of novel 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles was synthesized and their potential as imaging probes for Alzheimer's Disease (AD)-related amyloid plaque was evaluated in vitro and in vivo. In vitro binding affinities for Abeta1-40 peptide of several of these compounds were in the low-nanomolar range . The lowest K(i) of 9.3nM was found for N-(2-(4-(dimethylamino)phenyl)-1,3-benzoxazol-5-yl)-4-iodobenzamide (1e). Its (123)I-radiolabeled form ([(123)I]1e) was subsequently prepared by iododestannylation of the corresponding tributylstannyl precursor and evaluated in vivo in a baboon model using SPECT imaging. Contrary to our expectations, 1e did not cross the blood-brain barrier (BBB) to any significant extent.

Regional distribution and behavioral correlates of 5-HT(2A) receptors in Alzheimer's disease with [(18)F]deuteroaltanserin and PET.

Postmortem studies show reductions in brain serotonin 2A (5-HT(2A)) receptors in Alzheimer's disease (AD). Converging evidence also suggests that serotonergic dysregulation may contribute to behavioral symptoms that frequently occur in AD. This study aimed to define regional reductions in 5-HT(2A) binding in AD patients and to examine their behavioral correlates. Nine patients with probable AD and eight elderly controls were studied using a constant infusion paradigm for equilibrium modeling of [(18)F]deuteroaltanserin with positron emission tomography (PET). Region of interest analyses were performed on PET images coregistered to MRI scans. The outcome measures BP(P) (ratio of specific brain uptake to total plasma parent concentration) and BP(ND) (ratio of specific to nondisplaceable uptake) were obtained for pertinent cortical and subcortical regions. AD patients showed a statistically significant decrease in the anterior cingulate in both BP(P) and BP(ND), but in no other region. Within the AD patient sample, no significant correlations were observed between regional 5-HT(2A) binding and behavioral measures, including depressive and psychotic symptoms. These results confirm a reduction in cortical 5-HT(2A) receptors in AD, specifically in the anterior cingulate. However, in a limited AD patient sample, they fail to demonstrate a relationship between regional 5-HT(2A) binding and major behavioral symptoms.

Development and In Vivo Preclinical Imaging of Fluorine-18-Labeled Synaptic Vesicle Protein 2A (SV2A) PET Tracers.

PURPOSE: Synaptic vesicle protein 2A (SV2A) serves as a biomarker of synaptic density and positron emission tomography (PET) imaging of SV2A could provide a tool to assess progression of neurodegenerative diseases. Two tracers have primarily been reported and characterized in vivo: [11C]UCB-J and [18F]UCB-H. In early human studies, [11C]UCB-J showed promising results, while its F-18-labeled analogue [18F]UCB-H showed suboptimal specific signal in comparison to [11C]UCB-J. Considering the limited use of [11C]UCB-J to facilities with a cyclotron, having a F-18 variant would facilitate large, multicenter imaging trials. We have screened several F-18 derivatives of UCB-J in non-human primates and identified a promising F-18 PET candidate, [18F]MNI-1126, with additional investigations of the racemate [18F]MNI-1038, affording a signal comparable to [11C]UCB-J. PROCEDURES: F-18 derivatives of UCB-J and UCB-H were synthesized and administered to non-human primates for microPET imaging. Following screenings, [18F]MNI-1038 (racemate) and [18F]MNI-1126 (R-enantiomer) were identified with the highest signal and favorable kinetics and were selected for further imaging. Kinetic modeling with one- and two-tissue compartmental models, and linear methods were applied to PET data using metabolite-corrected arterial input function. Pre-block scans with levetiracetam (LEV, 10, 30 mg/kg, iv) were performed to determine the tracers' in vivo specificity for SV2A. Two whole-body PET studies were performed with [18F]MNI-1038 in one male and one female rhesus, and radiation absorbed dose estimates and effective dose (ED, ICRP-103) were estimated with OLINDA/EXM 2.0. RESULTS: All compounds screened displayed very good brain penetration, with a plasma-free fraction of ~ 40 %. [18F]MNI-1126 and [18F]MNI-1038 showed uptake and distribution the most consistent with UCB-J, while the other derivatives showed suboptimal results, with similar or lower uptake than [18F]UCB-H. VT of [18F]MNI-1126 and [18F]MNI-1038 was high in all gray matter regions (within animal averages ~ 30 ml/cm3) and highly correlated with [11C]UCB-J (r > 0.99). Pre-blocking of [18F]MNI-1126 or [18F]MNI-1038 with LEV showed robust occupancy across all gray matter regions, similar to that reported with [11C]UCB-J (~ 85 % at 30 mg/kg, ~ 65 % at 10 mg/kg). Using the centrum semiovale as a reference region, BPND of [18F]MNI-1126 reached values of up to ~ 30 to 40 % higher than those reported for [11C]UCB-J. From whole-body imaging average ED of [18F]MNI-1038 was estimated to be 22.3 µSv/MBq, with tracer being eliminated via both urinary and hepatobiliary pathways. CONCLUSIONS: We have identified a F-18-labeled tracer ([18F]MNI-1126) that exhibits comparable in vivo characteristics and specificity for SV2A to [11C]UCB-J in non-human primates, which makes [18F]MNI-1126 a promising PET radiotracer for imaging SV2A in human trials.

Synthesis, radiolabeling and baboon SPECT imaging of 2beta-carbomethoxy-3beta-(3'-[(123)I]iodophenyl)tropane ([(123)I]YP256) as a serotonin transporter radiotracer.

To develop a potential SPECT probe to evaluate the integrity of the serotoninergic system (5-HTT) whose dysfunction is linked to several disease conditions such as Parkinson's disease, Alzheimer's disease and depression, we report the synthesis, radiolabeling and in vivo baboon imaging of 2beta-carbomethoxy-3beta-(3'-[(123)I]iodophenyl) tropane (YP256, 6). The radiolabeling was performed by iododestannylation using sodium [(123)I]iodide and peracetic acid. Although the ligand displayed high selectivity for 5-HTT over dopamine transporter in vitro, SPECT imaging in baboons did not reveal selective 5-HTT accumulation in brain in vivo.

Human tobacco smokers in early abstinence have higher levels of beta2* nicotinic acetylcholine receptors than nonsmokers.

Nicotine, the addictive chemical in tobacco smoke, initiates its actions in brain through nicotinic acetylcholine receptors (nAChRs). In particular, nAChRs containing beta2-subunits (beta2*-nAChRs) the most prevalent subtype, mediate the reinforcing properties of nicotine. We hypothesized that abnormal numbers of beta2*-nAChRs during early abstinence contribute to the perpetuation of addiction to tobacco smoking. Using molecular imaging, specifically single-photon emission computed tomography with the nAChR agonist radiotracer [123I]5-IA-85380 ([123I]5-IA), we imaged beta2*-nAChR availability in human smokers. First, using nonhuman primates treated chronically with nicotine, we estimated the time interval necessary for smokers to abstain from smoking so that residual nicotine would not interfere with [123I]5-IA binding to the beta2*-nAChR as approximately 7 d. Thus, we imaged human smokers at 6.8 +/- 1.9 d (mean +/- SD) of abstinence. Abstinence was confirmed by daily assessments of urinary cotinine and expired carbon monoxide levels. In smokers, [123I]5-IA uptake was significantly higher throughout the cerebral cortex (26-36%) and in the striatum (27%) than in nonsmokers, suggesting higher beta2*-nAChR in recently abstinent smokers. Beta2*-nAChR availability in recently abstinent smokers correlated with the days since last cigarette and the urge to smoke to relieve withdrawal symptoms but not the severity of nicotine dependence, severity of nicotine withdrawal, or the desire to smoke. Higher brain beta2*-nAChR during early abstinence indicates that, when smokers quit smoking, they do so in the face of a significant increase in the receptors normally activated by nicotine. Greater beta2*-nAChR availability during early abstinence may impact the ability of smokers to maintain abstinence.

123I-5-IA-85380 SPECT imaging of nicotinic acetylcholine receptor availability in nonsmokers: effects of sex and menstrual phase.

UNLABELLED: The study of the effects of sex and hormones on brain chemistry and neurotransmission is of increasing importance as evidence emerges of sex differences in behavioral symptoms and treatment response in neuropsychiatric disorders. The nicotinic acetylcholine receptor (nAChR) system has been implicated in a variety of psychiatric disorders, including tobacco smoking, for which there is strong evidence supporting sex differences in behaviors and response to smoking cessation treatments. We examined the availability of nAChR containing the beta(2) subunit in healthy men and women and the influence of menstrual phase among women. METHODS: Ten men and 19 women nonsmokers underwent one (123)I-5-IA-85380 ((123)I-5-IA) SPECT scan and one MRI scan. A subset of 9 women, aged 18-39 y, underwent a second (123)I-5-IA scan. These 9 women were scanned during the early follicular (days 4-7 in 8 subjects and day 11 in 1 subject) and mid-luteal (days 19-25) phases of their menstrual cycle. Hormone levels were measured in all women to confirm the phase of the cycle. RESULTS: Regional brain activity (kBq/cm(3)) was higher (39%-54%) in women than in men nonsmokers. When regional brain activity was normalized to total plasma parent to correct for individual differences in radiotracer metabolism (V(T)'), differences of 10%-16% were observed, with women greater than men. In contrast, when regional brain activity was normalized to free plasma parent (V(T)), there was less than a 4% difference by sex in regional brain beta(2)-nAChR availability. These sex differences in kBq/cm(3) and V(T)' resulted from significantly higher levels of total plasma parent, free fraction (f(1)), and free plasma parent in women than in men nonsmokers. No differences in plasma measures or brain beta(2)-nAChR availability were observed across the menstrual cycle for any outcome measure. CONCLUSION: Overall, these findings demonstrate no significant difference in brain beta(2)-nAChR availability between men and women nonsmokers or across the menstrual cycle. Importantly, these findings demonstrate sex differences in radiotracer metabolism and plasma protein binding and highlight the critical need to measure plasma radiotracer levels and f(1) in studies that include both sexes.

[123I]5-IA-85380 SPECT imaging of beta2-nicotinic acetylcholine receptor availability in the aging human brain.

Human postmortem studies have reported decreases with age in high-affinity nicotine binding in brain. We have been investigating in vivo the availability of the beta(2)-containing nicotinic acetylcholine receptor (beta(2)-nAChR) in healthy nonsmokers (18-85 years of age) using [(123)I]5-IA-85380 SPECT imaging. Age and regional beta(2)-nAChR availability (V(T)(,)) have been observed to be inversely correlated in all brain regions analyzed, with decline ranging from 21% (cerebellum) to 36% (thalamus), or by up to 5% per decade of life. Preliminary results have confirmed postmortem reports of age-related decline in high-affinity nicotine binding with age and may elucidate the role of beta(2)-nAChRs in the cognitive decline associated with aging.