COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET

A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [11C]NNC112. We compared [11C]NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [11C]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [11C]NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia.     

PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756

NNC 756 ((+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine) is a new high affinity dopamine (DA) D1 receptor antagonist. Labeled with C-11, it has been used as a PET radiotracer to visualize D1 receptors both in striatal and extrastriatal areas, such as the prefrontal cortex. The goal of this study was to evaluate several methods for derivation of D1 receptor binding potential (BP) with [11C]NNC 756 in baboons, and to use these methods to assess the vulnerability of [11C]NNC 756 binding to competition by endogenous DA. A three-compartment model provided a good fit to PET data acquired following a single bolus injection. BP values obtained with this analysis were in good agreement with values derived from in vitro studies. BP values measured following injection of the potent DA releaser amphetamine (1 mg/kg, n=2) were similar to values measured under control conditions. Kinetic parameters derived from single bolus experiments were used to design a bolus plus continuous infusion administration protocol aimed at achieving a state of sustained binding equilibrium. Injection of amphetamine during sustained equilibrium did not affect [11C]NNC 756 binding. Similar results were observed with another D1 radiotracer, [11C]SCH 23390. Doses of amphetamine used in this study are known to reduce by 20-40% the binding potential of several D2 receptors radiotracers. Therefore, the absence of displacement of [11C]NNC 756 by an endogenous DA surge may indicate important differences between D1 and D2 receptors in vivo, such as differences in proportion of high affinity states not occupied by DA at baseline. These findings may also imply that a simple binding competition model is inadequate to account for the effects of manipulation of endogenous DA levels on the in vivo binding of radiolabeled antagonists.     

Characterization of in vivo pharmacokinetic properties of the dopamine D1 receptor agonist DAR-0100A in nonhuman primates using PET with [11C] NNC112 and [11C] raclopride

DAR-0100A, the active enantiomer of dihydrexidine, is a potent dopamine D1 agonist under investigation for treatment of cognitive impairment and negative symptoms of schizophrenia. We measured the dose–occupancy relationship for DAR-0100A at D1 receptors using positron emission tomography (PET) imaging in baboons with [¹¹C] NNC112 and its binding to D2 with [¹¹C] raclopride. Two baboons were scanned with [¹¹C] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [¹¹C] raclopride at baseline and after one dose of DAR-0100A. Occupancy (ΔBP_ND) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and ΔBP_ND. ΔBP_ND was larger in the striatum than in the cortex, consistent with reports showing that 25% of [¹¹C] NNC112 BP_ND in the cortex is attributed to 5-HT_2A. Plasma EC₅₀ estimates ranged from 150 to 550 ng/mL according to the constraints on the model. There was no detectable effect of DAR-0100A on [¹¹C] raclopride BP_ND. These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [¹¹C] NNC112 PET and binding of DAR-0100A to D2 will be negligible. This is the first demonstration with PET of a significant occupancy by a full D1 agonist in vivo.     

Increased microglial activation in patients with Parkinson disease using [18F]-DPA714 TSPO PET imaging

IntroductionIncreasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [¹¹C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [¹⁸F]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status.MethodsPD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [¹⁸F]-DPA714 and [¹¹C]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests.ResultsPD patients showed significantly higher [¹⁸F]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [¹¹C]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction).Conclusion[¹⁸F]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients.Trial registrationTrial registration: INFLAPARK, NCT02319382. Registered 18 December 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02319382.     

PET imaging of serotoninergic neurotransmission with [11C]DASB and [18F]altanserin after focal cerebral ischemia in rats

The use of selective serotonin reuptake inhibitors has shown functional improvement after stroke. Despite this, the role of serotoninergic neurotransmission after cerebral ischemia evolution and its involvement in functional recovery processes are still largely unknown. For this purpose, we performed in parallel in vivo magnetic resonance imaging and positron emission tomography (PET) with [¹¹C]DASB and [¹⁸F]altanserin at 1, 3, 7, 14, 21, and 28 days after middle cerebral artery occlusion (MCAO) in rats. In the ischemic territory, PET with [¹¹C]DASB and [¹⁸F]altanserin showed a dramatic decline in serotonin transporter (SERT) and 5-HT_2A binding potential in the cortex and striatum after cerebral ischemia. Interestingly, a slight increase in [¹¹C]DASB binding was observed from days 7 to 21 followed by the uppermost binding at day 28 in the ipsilateral midbrain. In contrast, no changes were observed in the contralateral hemisphere by using both radiotracers. Likewise, both functional and behavior testing showed major impaired outcome at day 1 after ischemia onset followed by a recovery of the sensorimotor function and dexterity from day 21 to day 28 after cerebral ischemia. Taken together, these results might evidence that SERT changes in the midbrain could have a key role in the functional recovery process after cerebral ischemia.     

Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility.

To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient (k3/k4). Both kinetic and graphic analyses provided BP and k3/k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k3/k4 by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90+/-0.06 (mean +/- SD of 12 regions) and 0.84+/-0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72+/-0.17 and 0.58+/-0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor density.     

In-vivo measurement of LDOPA uptake,dopamine reserve and turnover in the rat brain using [18F]FDOPA PET

Longitudinal measurements of dopamine (DA) uptake and turnover in transgenic rodents may be critical when developing disease-modifying therapies for Parkinson''s disease (PD). We demonstrate methodology for such measurements using [¹⁸F]fluoro-3,4-dihydroxyphenyl-L-alanine ([¹⁸F]FDOPA) positron emission tomography (PET). The method was applied to 6-hydroxydopamine lesioned rats, providing the first PET-derived estimates of DA turnover for this species. Control (n=4) and unilaterally lesioned (n=11) rats were imaged multiple times. Kinetic modeling was performed using extended Patlak, incorporating a k_loss term for metabolite washout, and modified Logan methods. Dopaminergic terminal loss was measured via [¹¹C]-(+)-dihydrotetrabenazine (DTBZ) PET. Clear striatal [¹⁸F]FDOPA uptake was observed. In the lesioned striatum the effective DA turnover increased, shown by a reduced effective distribution volume ratio (EDVR) for [¹⁸F]FDOPA. Effective distribution volume ratio correlated (r>0.9) with the [¹¹C]DTBZ binding potential (BP_ND). The uptake and trapping rate (k_ref) decreased after lesioning, but relatively less so than [¹¹C]DTBZ BP_ND. For normal controls, striatal estimates were k_ref=0.037±0.005 per minute, EDVR=1.07±0.22 and k_loss=0.024±0.003 per minute (30 minutes turnover half-time), with repeatability (coefficient of variation) ≤11%. [¹⁸F]fluoro-3,4-dihydroxyphenyl-L-alanine PET enables measurements of DA turnover in the rat, which is useful for developing novel therapies for PD.     

Amyloid imaging in aged and young macaques with [11C]PIB and [18F]FDDNP

[11C]PIB and [18F]FDDNP were examined on five aged and five young adult male rhesus macaques using positron emission tomography. Both tracers showed increased accumulation in the striatum, thalamus, cingulate and pons in the aged group. Compared to [11C]PIB, [18F]FDDNP showed higher accumulation in the cortical regions of aged animals as well as young animals. Although [18F]FDDNP may have possible usefulness for imaging, including other proteins, [11C]PIB may be better for amyloid imaging owing to lower non-specific binding.     

Striatal and extrastriatal dopamine release measured with PET and [18F] fallypride

The amphetamine challenge, in which positron emission tomography (PET) or single photon emission computed tomography radioligand binding following administration of amphetamine is compared to baseline values, has been successfully used in a number of brain imaging studies as an indicator of dopaminergic function, particularly in the striatum. [¹⁸F] fallypride is the first PET radioligand that allows measurement of the effects of amphetamine on D2/D3 ligand binding in striatum and extra‐striatal brain regions in a single scanning session following amphetamine. We scanned 15 healthy volunteer subjects with [¹⁸F] fallypride at baseline and following amphetamine (0.3 mg/kg) using arterial plasma input‐based modeling as well as reference region methods. We found that amphetamine effect was robustly detected in ventral striatum, globus pallidus, and posterior putamen, and with slightly higher variability in other striatal subregions. However, the observed effect sizes in striatum were less than those observed in previous studies in our laboratory using [¹¹C] raclopride. Robust effect was also detected in limbic extra‐striatal regions (hippocampus, amygdala) and substantia nigra, but the signal‐to‐noise ratio was too low to allow accurate measurement in cortical regions. We conclude that [¹⁸F] fallypride is a suitable ligand for measuring amphetamine effect in striatum and limbic regions, but it is not suitable for measuring the effect in cortical regions and may not provide the most powerful way to measure the effect in striatum. Synapse 64:350–362, 2010. © 2009 Wiley‐Liss, Inc.     

Imaging cortical dopamine D1 receptors using [11C]NNC112 and ketanserin blockade of the 5-HT2A receptors

[¹¹C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D₁ receptor (R) over the 5-HT_2A R in vitro, has shown lower selectivity in vivo, hampering measurement of D₁ R in the cortex. [¹¹C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [¹¹C]NNC112 in vivo D₁ R selectivity, and (2) develop a feasible methodology for imaging cortical D₁ R without contamination by 5-HT_2A R. Seven healthy volunteers underwent [¹¹C]NNC112 PET scans at baseline and after a 5-HT_2A R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BP_ND change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BP_ND in the cortical (∼30%) and limbic regions (∼20%) but not in the striatum, which contains a much lower amount of 5-HT_2A R. Therefore, ketanserin allows D₁ R signal to be detected by [¹¹C]NNC112 PET without significant 5-HT_2A R contamination. These data confirm the presence of a significant 5-HT_2A R contribution to cortical [¹¹C]NNC112 signal, and call for caution in the interpretation of published [¹¹C]NNC112 PET findings on cortical D₁ R in humans. In the absence of more selective ligands, [¹¹C]NNC112 PET with ketanserin can be used for cortical D₁ R imaging in vivo.     

Functional brain imaging in pure akinesia with gait freezing: [18F] FDG PET and [18F] FP‐CIT PET analyses

Pure akinesia with gait freezing (PAGF) has characteristic features, including freezing of gait and prominent speech disturbance without rigidity or tremor. The purpose of this study was to investigate changes in brain glucose metabolism and presynaptic dopaminergic function in PAGF. By using [¹⁸F] fluorodeoxyglucose (FDG) PET, 11 patients with PAGF were compared with 14 patients with probable progressive supranuclear palsy (PSP), 13 patients with Parkinson's disease (PD), and 11 normal controls. [¹⁸F] N‐(3‐fluoropropyl)‐2β‐carbon ethoxy‐3β‐(4‐iodophenyl) nortropane (FP‐CIT) PET was performed in 11 patients with PAGF and with 10 normal controls. The PAGF patients showed decreased glucose metabolism in the midbrain when compared with normal controls. PSP patients showed a similar topographic distribution of glucose hypometabolism with additional areas, including the frontal cortex, when compared with normal controls. The FP‐CIT PET findings in patients with PAGF revealed severely decreased uptake bilaterally in the basal ganglia. These findings suggest that both PAGF and PSP may be part of the same pathophysiologic spectrum of disease. However, the reason why PAGF manifests clinically in a different manner needs to be further elucidated. © 2008 Movement Disorder Society     

Pet imaging studies of dopamine D2 receptors: Comparison of [18F]N-Methylspiperone; and the benzamide analogues [18F]MABN and [18F]MBP in baboon brain

A series of positron emission tomography (PET) imaging studies was conducted in a baboon with the benzamide derivatives [¹⁸F]2,3-dimethoxy N-9-(4-fluorobenzyl)-9-azabicyclo[3.3.1]nonan-3β-yl]benzamide ([¹⁸F]MABN) and [¹⁸F]2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]benzamide ([¹⁸F]MBP). Studies were also conducted with the butyrophenone [¹⁸F]N-methylspiperone (NMSP) for comparison. Tissue-time activity curves of [¹⁸F]MABN are similar to those of [¹⁸F]NMSP since both compounds displayed approximately the same uptake in the basal ganglia and displayed irreversible binding kinetics in vivo. However, the rapid rate of clearance from the cerebellum and high basal ganglia: cerebellum ratio of [¹⁸F]MABN indicate that this compound has a much lower amount of nonspecific binding than [¹⁸F]NMSP. [¹⁸F]MBP displayed a higher uptake in the basal ganglia relative to [¹⁸F]NMSP and [¹⁸F]MABN and exhibited reversible binding kinetics in vivo. This property of [¹⁸F]MBP is desirable since the uptake of radioactivity in D₂-rich ligands is less likely to be influenced by changes in cerebral blood flow. The current data suggest that both [¹⁸F]MABN and [¹⁸F]MBP are promising ligands for studying dopamine D₂ receptors with PET. © 1995 Wiley-Liss, Inc.     

In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET.

OBJECTIVE: In-vivo imaging of beta-amyloid plaques (Abeta) may improve both early detection of Alzheimer disease (AD) and efficacy assessment of new treatments for AD. The authors' aim was to develop a novel Abeta-specific positron-emission tomography (PET) tracer. METHODS: Five female AD patients (54-77 years old) and six healthy female comparison subjects (53-74 years old), completed 2-hour PET scans after intravenous injection of 10 mCi of both the stilbene [11C]SB-13 and the benzothiazole [11C]6-OH-BTA-1 (also known as [11C]PIB). Kinetic analyses were performed on the resulting time-activity curves to derive Abeta binding-potential estimates, using as input function either the unmetabolized tracer concentration in venous plasma from a two-tissue compartment model or the density of radioactivity in the cerebellum. Authors compared the binding characteristics of the two radiotracers. RESULTS: The two radiotracers demonstrated similar binding properties with respect to regional distribution of retention (increased retention in the frontal and posterior temporal-inferior parietal association cortices in the AD patients, but not in the comparison subjects). Our preliminary PET data indicate that [11C]SB-13 may be similar to [11C]PIB in discriminating AD patients from comparison subjects. CONCLUSIONS: [11C]SB-13 is an effective PET tracer for fibrillar Abeta imaging in vivo, with similar performance as [11C]PIB. Future research directions include evaluation of tracer in larger AD patient samples and in subjects with amnestic mild cognitive impairment, evaluation of arterial input function, and comparison with other tracers, such as [18F]FDG as they relate to cognitive functioning.     

Comparison of [11C]flumazenil and [18F]FDG as PET markers of epileptic foci.

Recent PET results indicate that the benzodiazepine (BZ) receptor density measured with the BZ receptor antagonist [11C]flumazenil is reduced in human epileptic foci. The present study examines the applicability of this finding in the presurgical investigation of patients with intractable partial epilepsy. In eight patients, the PET measurements were performed after injection of the BZ receptor antagonist [11C]flumazenil and [2-18F]2-deoxy-2-fluoro-D-glucose ([18F]FDG)--a tracer for measurements of the rate of regional glucose metabolism. The focus localising ability of the two PET tracers was examined using extra--and intracranial EEG recordings as reference. The focus was first determined visually on the PET images obtained after a bolus injection of each of the PET tracers. Its anatomical localisation and spatial delimitation was then evaluated for each patient with a computerised anatomical brain atlas. [11C]flumazenil was found to be a more sensitive and accurate focus localiser than [18F]FDG. This observation was valid both for quantified and non-quantified images. In the preoperative diagnosis of epileptic foci, the PET measurements of BZ receptors may be a suitable and, in some cases, superior method to the generally used "[18F]FDG-PET" method.     

Comparison of [11C]UCB-J and [18F]FDG PET in Alzheimer’s disease: A tracer kinetic modeling study

[¹¹C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer’s disease (AD). We compared [¹¹C]UCB-J binding for synaptic density and [¹⁸F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K₁ or R₁ for [¹¹C]UCB-J perfusion, V_T (volume of distribution) or DVR to cerebellum for [¹¹C]UCB-J binding to SV2A; and K_i or K_iR to cerebellum for [¹⁸F]FDG metabolism. [¹¹C]UCB-J binding and [¹⁸F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD –compared to CN participants. However, the magnitude of reduction of [¹¹C]UCB-J binding in neocortical regions was less than that observed with [¹⁸F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [¹¹C]UCB-J perfusion showed a similar pattern to [¹⁸F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.     

PET studies of net blood-brain clearance of FDOPA to human brain: age-dependent decline of [18F]fluorodopamine storage capacity.

Conventional methods for the graphical analysis of 6-[(18)F]fluorodopa (FDOPA)/positron emission tomography (PET) recordings (K(in)(app)) may be prone to negative bias because of oversubtraction of the precursor pool in the region of interest, and because of diffusion of decarboxylated FDOPA metabolites from the brain. These effects may reduce the sensitivity of FDOPA/PET for the detection of age-related changes in dopamine innervations. To test for these biasing effects, we have used a constrained compartmental analysis to calculate the brain concentrations of the plasma metabolite 3-O-methyl-FDOPA (OMFD) during 120 mins of FDOPA circulation in healthy young, healthy elderly, and Parkinson's disease subjects. Calculated brain OMFD concentrations were subtracted frame-by-frame from the dynamic PET recordings, and maps of the FDOPA net influx to brain were calculated assuming irreversible trapping (K(app)). Comparison of K(in)(app) and K(app) maps revealed a global negative bias in the conventional estimates of FDOPA clearance. The present OMFD subtraction method revealed curvature in plots of K(app) at early times, making possible the calculation of the corrected net influx (K) and also the rate constant for diffusion of decarboxylated metabolites from the brain (k(loss)). The effective distribution volume (EDV(2); K/k(loss)) for FDOPA, an index of dopamine storage capacity in brain, was reduced by 85% in putamen of patients with Parkinson's disease, and by 58% in the healthy elderly relative to the healthy young control subjects. Results of the present study support claims that storage capacity for dopamine in both caudate and putamen is more profoundly impaired in patients with Parkinson's disease than is the capacity for DOPA utilization, calculated by conventional FDOPA net influx plots. The present results furthermore constitute the first demonstration of an abnormality in the cerebral utilization of FDOPA in caudate and putamen as a function of normal aging, which we attribute to loss of vesicular storage capacity.     

Risk for Parkinson’s disease: twin studies for the detection of asymptomatic subjects using [18F]6-fluorodopa PET

Positron emission tomography (PET) studies were carried out with [¹⁸F]6-fluorodopa ([¹⁸F]6-FD) in monozygotic (MZ) and dizygotic (DZ) twins for the clarification of dopaminergic function. Four MZ and four DZ pairs of twins, each pair consisting of a parkinsonian index case and an asymptomatic co-twin, were collected from the Nationwide Twin Cohort. The control group comprised 14 healthy volunteers. [¹⁸F]6-FD PET examinations with a Siemens/CTI 931/08 scanner were performed dynamically over 90 min. The regions-of-interest analysis included the caudate, the putamen and the occipital reference regions. Patlak plots were calculated using occipital tissue input function. The accumulation of [¹⁸F]6-FD in the putamen of the asymptomatic co-twins was significantly lower than that in the normal subjects. This result implies that there may be a preclinical stage of Parkinson’s disease in the apparently normal co-twins at the time of the PET study.