Publications (6) View all
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Article: Brain uptake and distribution of the dopamine D(3) /D(2) receptor partial agonist [(11) C]Cariprazine: An In Vivo positron emission tomography study in non-human primates.
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ABSTRACT: Cariprazine is a dopamine D(3) /D(2) receptor partial agonist antipsychotic candidate, which binds with high affinity to dopamine D(3) and D(2) receptors (with approximately 10-fold higher in vitro affinity to D(3) vs. D(2) receptors) and with moderate affinity to 5-HT(1A) receptors. The main objective of the present molecular imaging investigation was to evaluate the uptake and reversible binding of 11-C labeled cariprazine in the non-human primate brain, in relation to the known distributions of dopamine D(2) and D(3) receptors. We examined the brains of two cynomolgus monkeys at baseline condition as well as during a pharmacological blocking condition, using unlabeled cariprazine or raclopride as blockers before injection of [(11) C]cariprazine. Of the total injected radioactivity, ∼7 % entered the brain and ∼3 % - 4 % remained in the brain after 90 minutes, indicating good blood brain barrier penetration and slow washout. It was possible to block cariprazine binding with unlabeled cariprazine and raclopride indicating that [(11) C]cariprazine binds to dopamine D(3) /D(2) receptors. Non-displaceable binding potential (BP(ND) ) measurements, using a simplified reference tissue model (SRTM) and cerebellum as the reference region, yielded values of approximately 1.5 and 0.3 in the striatum and thalamus, respectively. Striatum BP(ND) values were reduced by 80% and 85% following pre-treatment with 0.1 mg/kg IV injection of unlabeled cariprazine and 1 mg/kg IV injection of unlabeled raclopride, respectively. The data confirm that cariprazine, a novel antipsychotic drug candidate, enters the non-human primate brain readily and binds to dopamine D(3) /D(2) receptors. Furthermore, in PET imaging [(11) C]cariprazine can effectively visualize dopamine D(3) /D(2) receptors in the non-human primate brain. © 2012 Wiley Periodicals, Inc.Synapse 12/2012; · 2.94 Impact Factor -
Article: Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: a PET study with the TSPO molecular imaging biomarker [((11))C]vinpocetine.
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ABSTRACT: Although there is increasing evidence for microglial activation after an ischaemic stroke in the infarct core and the peri-infarct region, the "evolution" of the process in stroke patients is poorly known. Using PET and [((11))C]vinpocetine, we measured the regional changes of TSPO in the brain of nine ischaemic stroke patients up to 14weeks after the insult. Already a week after stroke there was an increased radioligand uptake, indicating the up-regulation of TSPO and the presence of activated microglia, in both the ischaemic core and the peri-infarct zone. This increased activation showed a steady decrease with post stroke time. The proportion between %SUV values in the peri-infarct zone and the ischaemic core increased with time. There were no time-dependent TSPO activity changes in other regions, not affected directly by the stroke. The present observations demonstrate that increased regional microglia activation, as a consequence of stroke, can be visualised with PET, using the TSPO molecular imaging biomarker [((11))C]vinpocetine. The evolution of this microglial activation shows a time dependent decrease the gradient of which is different between the peri-infarct zone and the ischaemic core. The findings indicate an increased microglial activation in the peri-stroke region for several weeks after the insult.Journal of the neurological sciences 07/2012; 320(1-2):110-7. · 2.32 Impact Factor -
Article: In vivo evaluation in cynomolgus monkey brain and metabolism of [¹⁸F]fluorodeprenyl: a new MAO-B pet radioligand.
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ABSTRACT: In this study, we evaluated the in vivo characteristics of a new monoamine oxidase type B (MAO-B) radioligand, [¹⁸F]fluorodeprenyl, by positron emission tomography (PET) in two cynomolgus monkeys. The brain uptake of [¹⁸F]fluorodeprenyl was more than 7% (600% SUV) of the total injected radioactivity and similar to that of [¹¹C]deprenyl, an established MAO-B radioligand. The highest uptake was observed in the striatum, one of the MAO-B-rich regions, with a peak at approximately 2-3 min after injection, followed by lower uptake in the thalamus and the cortex and lowest uptake in the cerebellum. Brain uptake of [¹⁸F]fluorodeprenyl was largely inhibited by preadministration of the MAO-B inhibitor, L-deprenyl, whereas clorgyline, a MAO Type A blocker, had no significant inhibitory effect, thus demonstrating selectivity for MAO-B. [¹⁸F]Fluorodeprenyl showed relatively slow metabolism with the presence of two radiometabolite peaks with similar retention time as the labeled metabolites of [¹¹C]deprenyl. These results suggest that [¹⁸F]fluorodeprenyl is a potential PET radioligand for visualization of MAO-B activity.Synapse 11/2011; 66(4):323-30. · 2.94 Impact Factor -
Article: Imaging of the striatal and extrastriatal dopamine transporter with (18)F-LBT-999: quantification, biodistribution, and radiation dosimetry in nonhuman primates.
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ABSTRACT: The aim of this study was to evaluate the quantification, biodistribution, and radiation dosimetry of the novel dopamine transporter (DAT) radioligand (18)F-(2S,3S)-methyl 8-((E)-4-fluorobut-2-en-1-yl)-3-(p-tolyl)-8-azabicyclo[3.2.1]octane-2-carboxylate ((18)F-LBT-999) in nonhuman primates. The brain study was conducted in 4 female rhesus monkeys. PET measurements were conducted for 243 min using the high-resolution research tomograph (HRRT) with the measurement of the metabolite-corrected arterial input function and protein binding. Quantification was performed with kinetic analysis using 2-tissue- and 1-tissue-compartment models, with Logan graphical analysis and with different reference tissue models. The outcome measures were total distribution volume (V(T)), nondisplaceable distribution volume (V(ND)), binding potential relative to the free concentration of radioligand in plasma (BP(F)), and binding potential relative to the concentration of nondisplaceable radioligand in tissue (BP(ND)) = V(T) - V(ND)/V(ND) using the cerebellum as a reference region. For the biodistribution and radiation dosimetry, 2 female cynomolgus monkeys were studied. Whole-body PET scans were obtained using a PET/CT system for approximately 250 min. Estimates of the absorbed radiation dose in humans were calculated using OLINDA/EXM software. (18)F-LBT-999 showed good brain uptake (300% standardized uptake value) and regional distribution according to known DAT density. The 2-tissue-compartment model was the preferred model for the quantification. Late peak equilibrium (120-140 min) and slow washout were observed in the striatum, with high variability of V(T), BP(F), and BP(ND). When the different models were compared with the 2-tissue-compartment model, the underestimation of V(T) or BP(ND) was larger in the caudate and putamen than in the midbrain and thalamus. The reference tissue models were suitable for the quantification. The whole-body distribution study showed that the main routes of excretion of (18)F-LBT-999 were the urinary and gastrointestinal systems, with the bladder being the critical organ. Accumulation of (18)F-LBT-999 was found in the bone and skull, with a relatively high dose estimated for the osteogenic cells. The range of calculated effective dose was 0.021-0.022 mSv/MBq. (18)F-LBT-999 seemed to be a suitable PET radioligand for the DAT quantification, particularly for extrastriatal regions. The skull uptake did not seem to be a limitation for brain imaging. The calculated dosimetry estimates based on data in nonhuman primates seemed comparable with those of other clinically used (18)F-labeled radioligands, for example, (18)F-FDG (0.024-0.027 mSv/MBq).Journal of Nuclear Medicine 08/2011; 52(8):1313-21. · 6.38 Impact Factor -
Article: Age and disease related changes in the translocator protein (TSPO) system in the human brain: positron emission tomography measurements with [11C]vinpocetine.
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ABSTRACT: The main objectives of the present study were (i) to measure density changes of activated microglia and the peripheral benzodiazepine receptor/translocator protein (TSPO) system during normal ageing in the human brain with positron emission tomography (PET) using the TSPO molecular imaging biomarker [(11)C]vinpocetine and (ii) to compare the level and pattern of TSPO in Alzheimer (AD) patients with age matched healthy subjects, in order to assess the biomarker's usefulness as a diagnostic imaging marker in normal (ageing) and pathological (AD) up-regulation of microglia. PET measurements were made in healthy volunteers, aged between 25 and 78 years, and AD patients, aged between 67 and 82 years, using [(11)C]vinpocetine as the tracer. Global and regional quantitative parameters of tracer uptake and binding, including time activity curves (TAC) of standard uptake values (%SUV), binding affinity parameters, intensity spectrum and homogeneity of the uptake distribution were measured and analysed. Both %SUV and binding values increased with age linearly in the whole brain and in all brain regions. There were no significant differences between the %SUV values of the AD patients and age matched control subjects. There were, however, significant differences in %SUV values in a large number of brain regions between young subjects and old subjects, as well as young subjects and AD patients. The intensity spectrum analysis and homogeneity analysis of the voxel data show that the homogeneity of the %SUV values decreases with ageing and during the disease, whereas the centre of the intensity spectrum is shifted to higher %SUV values. These data indicate an inhomogeneous up-regulation of the TSPO system during ageing and AD. These changes were significant between the group of young subjects and old subjects, as well as young subjects and AD patients, but not between old subjects and AD patients. The present data indicate that [(11)C]vinpocetine may serve as a molecular imaging biomarker of the activity of the TSPO system and, consequently, of the up-regulation of microglia during ageing and in neuroinflammatory diseases. However, the global and regional brain %SUV values between AD patients and age matched controls are not different from each other. The disease specific changes, measured with [(11)C]vinpocetine in AD, are significantly different from those measured in age matched controls only if the inhomogeneities in the uptake pattern are explored with advanced mathematical techniques. For this reason, PET studies using [(11)C]vinpocetine, as molecular imaging biomarker, can efficiently visualise the activation of microglia and the up-regulation of TSPO during ageing and in diseased brains with the help of an appropriate inhomogeneity analysis of the radioligand's brain uptake pattern.NeuroImage 02/2011; 56(3):1111-21. · 5.89 Impact Factor
