Olivier Barret

How affected is oxygen metabolism in DWI lesions? A combined acute stroke PET-MR study

Objective: To use back-to-back diffusion-weighted imaging (DWI) and PET to obtain quantitative measures of the cerebral metabolic rate of oxygen (CMRO2) within DWI lesions, and to assess the perfusion-metabolism coupling status by measuring the cerebral blood flow and the oxygen extraction fraction within DWI lesions. Methods: Six prospectively recruited acute carotid-territory stroke patients completed the imaging protocol, which was commenced 7 to 21 hours from onset and combined DWI derived from state-of-the-art diffusion tensor imaging sequencing using a 3-T magnet and fully quantitative 15O-PET. The PET variables were obtained in individual DWI lesions in each patient. Results: Across patients, the CMRO2 was reduced in the DWI lesion relative to mirror (mean reduction 39.5%; p = 0.028). Examining individual DWI lesions, however, revealed considerable variability in the extent of this CMRO2 reduction. The flow–metabolism coupling pattern underlying the DWI lesion was also variable, including ongoing ischemia, mild oligemia, and partial or complete reperfusion. Discussion: Diffusion-weighted imaging (DWI) lesions generally reflect substantial disruption of energy metabolism. However, the degree of metabolic disruption is variable, indicating DWI lesions may not always represent irreversibly damaged tissue. Finally, because DWI lesions can persist despite reperfusion, assessment of perfusion is necessary for interpretation of DWI changes in acute stroke.

Positron emission tomography using 18F-labelled endothelin-1 reveals prevention of binding to cardiac receptors owing to tissue-specific clearance by ETB receptors in vivo

1 Our aim was to synthesise an 18F analogue of endothelin‐1 (ET‐1), to dynamically image ET receptors in vivo by positron emission tomography (PET) and to elucidate the function of the ETB subtype as a clearing receptor in organs expressing high densities including kidney and lung. 2 [18F]‐ET‐1 was characterised in vitro and bound with a single subnanomolar affinity (KD=0.43±0.05 nM, Bmax=27.8±2.1 fmol mg−1 protein) to human left ventricle (n=4). 3 The in vivo distribution of [18F]‐ET‐1 in anaesthetised rats was measured using a dedicated small animal PET scanner (microPET) and ex vivo analysis. 4 Dynamic PET data demonstrated that high levels of radioligand accumulated rapidly in the lung, kidney and liver, consistent with receptor binding. The in vivo distribution correlated with the anatomical localisation of receptors detected in vitro using [125I]‐ET‐1. However, the receptor density visualised in the heart was unexpectedly low compared with that predicted from the in vitro measurements. 5 [18F]‐ET‐1 binding in lungs could not be displaced by the ETB selective antagonist BQ788, in agreement with the proposed internalisation of ET‐1 by ETB receptors. In contrast, infusion of BQ788 prior to injecting [18F]‐ET‐1 significantly reduce the amount of radioligand visualised in the ETB rich lung and kidney by 85% (P<0.05, n=3) and 55% (P<0.05, n=3), respectively. 6 Under conditions of ETB receptor blockade, the heart could be visualised by microPET imaging. 7 These results suggest that clearance by ETB receptors in the lung and kidney prevents binding of ET‐1 to receptors in the heart.

18 F-Endothelin-1, a positron emission tomography (PET) radioligand for the endothelin receptor system: radiosynthesis and in vivo imaging using microPET

Positron emission tomography (PET) is a powerful technique with the sensitivity to image and quantify receptor-bound radioligands in vivo. Recent progress in PET scanner technology has resulted in the development of dedicated tomographs designed for small animals, with resolution that allows the delineation of discrete organs and their larger substructures in rats and mice. Our aim was to determine whether endothelin-1 (ET-1) could be labelled with (18)F, and whether the resulting (18)F-ET-1 would have the required pharmacokinetic properties to permit binding and imaging of ET receptors in vivo. (18)F-ET-1 could be produced in a total radiochemical yield of 5.9+/-0.7% in 207+/-3 min (n=20). Specific radioactivities were in the range 220-370 GBq/micromol, and the radiochemical purity of the isolated (18)F-ET-1 was >95%. In vivo distribution in the rat was studied using microPET. High levels of (18)F-ET-1 uptake were found in lung and kidney, whereas liver showed moderate levels of uptake. The resolution of the microPET scanner was sufficient to differentiate heterogeneous uptake in subrenal structures in the rat.

Monte carlo simulation and scatter correction of the GE advance PET scanner with SimSET and Geant4

For Monte Carlo simulations to be used as an alternative solution to perform scatter correction, accurate modelling of the scanner as well as speed is paramount. General-purpose Monte Carlo packages (Geant4, EGS, MCNP) allow a detailed description of the scanner but are not efficient at simulating voxel-based geometries (patient images). On the other hand, dedicated codes (SimSET, PETSIM) will perform well for voxel-based objects but will be poor in their capacity of simulating complex geometries such as a PET scanner. The approach adopted in this work was to couple a dedicated code (SimSET) with a general-purpose package (Geant4) to have the efficiency of the former and the capabilities of the latter. The combined SimSET+Geant4 code (SimG4) was assessed on the GE Advance PET scanner and compared to the use of SimSET only. A better description of the resolution and sensitivity of the scanner and of the scatter fraction was obtained with SimG4. The accuracy of scatter correction performed with SimG4 and SimSET was also assessed from data acquired with the 20 cm NEMA phantom. SimG4 was found to outperform SimSET and to give slightly better results than the GE scatter correction methods installed on the Advance scanner (curve fitting and scatter modelling for the 300-650 keV and 375-650 keV energy windows, respectively). In the presence of a hot source close to the edge of the field of view (as found in oxygen scans), the GE curve-fitting method was found to fail whereas SimG4 maintained its performance.

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: 18F-MNI-659 and 18F-MNI-654

Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione (18F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione (18F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A. Methods: Eleven healthy volunteers participated in this study (18F-MNI-654 test–retest, 2 men; 18F-MNI-659 test–retest, 4 men and 1 woman; 18F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for 18F-MNI-654 and over 3.5 h for 18F-MNI-659, and pharmacokinetic modeling with plasma- and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for 18F-MNI-659 and radiation dosimetry estimated with OLINDA. Results: Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time–activity data demonstrated that 18F-MNI-654 kinetics were much slower than 18F-MNI-659 kinetics. For 18F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BPND), supporting noninvasive quantification, with test–retest variability less than 10% and intraclass correlation greater than 0.9. The 18F-MNI-659 effective dose was estimated at 0.024 mSv/MBq. Conclusion: PET imaging in the human brain with 2 novel PDE10A 18F tracers is being reported. Noninvasive quantification of 18F-MNI-659 with the simplified reference tissue model using the cerebellum as a reference is possible. In addition, 18F-MNI-659 kinetics are fast enough for a good estimate of BPND with 90 min of data, with values around 3.0 in the basal ganglia. Finally, 18F-MNI-659 dosimetry is favorable and consistent with values reported for other PET radiotracers currently used in humans.

The Phosphodiesterase 10 Positron Emission Tomography Tracer, [18F]MNI-659, as a Novel Biomarker for Early Huntington Disease

IMPORTANCE In Huntington disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages. OBJECTIVE To evaluate whether [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD. DESIGN, SETTING, AND PARTICIPANTS A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [18F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Binding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei. RESULTS Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntingtons Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [18F]MNI-659 uptake than did the HV cohort (mean, -48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, -47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [18F]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05). CONCLUSIONS AND RELEVANCE As a promising striatal imaging biomarker, [18F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.

Local Relationships Between Restricted Water Diffusion and Oxygen Consumption in the Ischemic Human Brain

Background and Purpose— MR is widely used to depict still ischemic but viable tissue in acute stroke. However, the relationship between the apparent diffusion coefficient (ADC) and energy failure from reduced oxygen supply are unknown in man. Methods— Acute carotid-territory stroke patients were studied prospectively with both diffusion tensor–imaging and back-to-back steady-state 15O-PET. Substantial numbers of voxels with oxygen extraction fraction >0.70 (ie, significant ongoing hypoxia) were identified in 3 patients (imaged at 7, 16 and 21 hours after stroke onset). In this voxel population, the quantitative relationships between the ADC and cerebral metabolic rate of oxygen (CMRO2), and ADC and cerebral blood flow (CBF), were assessed. Results— The ADC remained essentially unchanged until CBF reached values ≈20 mls/100g per min, beyond which it declined linearly. In contrast, except when severely reduced, the ADC was a poorer predictor of CMRO2. For both CBF and CMRO2, however, the relationship with ADC became steeper with longer times since onset, ie, the same ADC reflected lower perfusion and CMRO2 with elapsed time. Conclusions— Despite the small sample and late times from stroke onset, the findings indicate that the degree of restricted water diffusion reliably reflects the severity of oxygen deprivation below the penumbral threshold but is less strongly related to metabolic disruption, which may explain why the ADC does not reliably predict tissue outcome. However, the same degree of diffusion restriction may correspond to greater severity of tissue disruption with elapsing time, which has relevance for stroke therapy. Time elapsed since stroke onset should be taken into account when interpreting ADC declines and in voxel-based infarct prediction models.

Synthesis and preliminary evaluation of a new fluorine-18 labelled triazine derivative for PET imaging of cannabinoid CB2 receptor

Cannabinoid CB2 PET tracers are considered as a promising alternative to PBR/TSPO tracers for the in-vivo imaging of neuroinflammation. We describe here the synthesis and characterization of compound 3, a new potent and brain penetrating CB2 ligand based on an original triazine template. The PET tracer [(18)F]-dideutero-3 was prepared in a three steps radiosynthesis, and demonstrated significant uptake in rhesus macaque and baboon brain with a maximum SUV of about 0.7-0.9g/mL, followed by a moderate washout over time.

Change in PDE10 across early Huntington disease assessed by [18F]MNI-659 and PET imaging.

Objective: To evaluate whether striatal [18F]MNI-659 PET imaging of phosphodiesterase 10A (PDE10) serves as a sensitive and reliable biomarker of striatal neurodegeneration in a longitudinal cohort of participants with early Huntington disease (HD). Methods: A cohort of participants with HD, including both participants premanifest or manifest with motor signs, underwent clinical assessments, genetic determination, and 2 [18F]MNI-659 PET imaging sessions approximately 1 year apart. Eleven healthy control (HC) participants underwent clinical assessments and [18F]MNI-659 PET imaging once. Striatal binding potentials (BPnd) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between baseline and follow-up imaging. Clinical measures of HD severity were assessed at each visit. Results: Eight participants with HD (6 manifest; 2 premanifest) participated. Of those with manifest HD, all had relatively early stage disease (stage 1, n = 2; stage 2, n = 4) and a Unified Huntingtons Disease Rating Scale total motor score <45. As expected, the HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of that seen in HC. On follow-up scans, [18F]MNI-659 uptake declined in the putamen and caudate nucleus in all 8 participants. The mean annualized rates of decline in signal in the caudate, putamen, and globus pallidus and the putamen were 16.6%, 6.9%, and 5.8%, respectively. In HC, the annualized reduction in signal in striatal regions was less than 1%. Conclusion: Longitudinal data in this small cohort of participants with early HD support [18F]MNI-659 PET imaging of PDE10 as a useful biomarker to track HD disease progression.

Kinetic Modeling of the Tau PET Tracer 18F-AV-1451 in Human Healthy Volunteers and Alzheimer's Disease Subjects

18F-AV-1451 is currently the most widely used of several experimental tau PET tracers. The objective of this study was to evaluate 18F-AV-1451 binding with full kinetic analysis using a metabolite-corrected arterial input function and to compare parameters derived from kinetic analysis with SUV ratio (SUVR) calculated over different imaging time intervals. Methods: 18F-AV-1451 PET brain imaging was completed in 16 subjects: 4 young healthy volunteers (YHV), 4 aged healthy volunteers (AHV), and 8 Alzheimer disease (AD) subjects. Subjects were imaged for 3.5 h, with arterial blood samples obtained throughout. PET data were analyzed using plasma and reference tissue–based methods to estimate the distribution volume, binding potential (BPND), and SUVR. BPND and SUVR were calculated using the cerebellar cortex as a reference region and were compared across the different methods and across the 3 groups (YHV, AHV, and AD). Results: AD demonstrated increased 18F-AV-1451 retention compared with YHV and AHV based on both invasive and noninvasive analyses in cortical regions in which paired helical filament tau accumulation is expected in AD. A correlation of R2 > 0.93 was found between BPND (130 min) and SUVR-1 at all time intervals. Cortical SUVR curves reached a relative plateau around 1.0–1.2 for YHV and AHV by approximately 50 min, but increased in AD by up to approximately 20% at 110–130 min and approximately 30% at 160–180 min relative to 80–100 min. Distribution volume (130 min) was lower by 30%–35% in the YHV than AHV. Conclusion: Our data suggest that although 18F-AV-1451 SUVR curves do not reach a plateau and are still increasing in AD, an SUVR calculated over an imaging window of 80–100 min (as currently used in clinical studies) provides estimates of paired helical filament tau burden in good correlation with BPND, whereas SUVR sensitivity to regional cerebral blood changes needs further investigation.