[en] Complete text of publication follows: Objectives: P-glycoprotein (ABCB1) is the most studied ATP-binding cassette (ABC) transporter expressed at the blood-brain barrier (BBB). A powerful method to study P-gp function at the BBB is Positron Emission Tomography (PET) imaging in combination with radiolabeled P-gp substrate radiotracers. Currently available radiotracers are high-affinity P-gp substrates and convincingly highlight this transporter as a functional component of the BBB, which restricts the influx of its substrates from blood to the brain. Many CNS-active drugs, such as metoclopramide, were shown to be weak P-gp substrates and nonetheless show sufficient permeability to cross the BBB and exert CNS effects. The impact of P-gp on the brain kinetics of such weak substrates is not known. Methods We have recently shown the feasibility of PET imaging using ¹¹C-metoclopramide to measure in vivo P-gp function at the rodent BBB. ¹¹C-metoclopramide showed good specificity towards P-gp, suitable radiochemical purity of the PET signal in the brain (absence of radiometabolites in the brain) and lack of specific binding to other target structures in the brain. In the present study, ¹¹C-metoclopramide PET imaging was performed in non-human primates, a relevant animal model of the human BBB in terms of P-gp expression. Brain ¹¹C-metoclopramide (298.12 ± 44.13 MBq) PET acquisitions (60 min), including the measurement of the metabolite-corrected arterial input function, were performed in 4 anesthetized baboons (propofol). Experiments were performed in each animal in the absence (baseline) and the presence of an i.v infusion protocol allowing for constant and controlled plasma concentrations of the potent P-gp inhibitor tariquidar (TQD). PET images were co-registered onto corresponding MR images for each baboon to generate corresponding time-activity curves in selected brain regions. Kinetic modeling was performed using a 1-tissue compartment model (1-TCM) to estimate the influx (K1; mL/min/cm³) and efflux (k2; min^-1) rate constants and the total volume of distribution (VT = K1/k2 in the 1-TCM; mL/cm³). The wash-out of ¹¹C-metoclopramide from the brain was also described by the elimination slope kE (min-1), graphically measured from the Log-transformed PET kinetics from 30 to 60 min. Outcome parameters were statistically compared using a 2-way ANOVA with 'treatment' and 'brain regions' as factors. Results Baseline PET images showed the brain distribution of ¹¹C-metoclopramide-associated radioactivity, which was homogeneously distributed among brain regions. TQD increased the brain uptake of ¹¹C-metoclopramide and notably decreased its wash-out from the brain with a significant 1.5±0.2-fold decrease in kE (p≤0.01). PET kinetics were accurately estimated using the 1-TC model. Compared with baseline (VT = 4.3±0.5 mL.cM^-3), TQD significantly increased the brain distribution of ¹¹C-metoclopramide (VT = 8.7±0.5 mL.cM^-3, p≤0.001). This increase in VT was due to a significant 1.3±0.1-fold increase in K1 (p≤0.05) and a 1.6 ± 0.1-fold decrease in k2 (p≤0.001). The effect was homogeneous across tested brain regions. Conclusion Using ¹¹C-metoclopramide PET imaging in baboons, we showed that P-gp does not solely act as a 'barrier' to limit the brain penetration of xenobiotics from the blood. P-gp also mediates the clearance of its substrates back to the blood, thus providing an additional dynamic system to limit overall brain exposure

[en] Complete text of publication follows: Objectives: Efflux transporters of the ATP-binding cassette (ABC) superfamily, namely the P-glycoprotein (ABCB1) and the Breast Cancer Resistance Protein (ABCG2) form the functional component of the blood-brain barrier (BBB). They are known to restrict the transendothelial permeation of most tyrosine kinase inhibitors (TKIs) such as erlotinib through the intact BBB, thus limiting the clinical perspective of TKI-based therapy against brain malignancies. However, physical BBB disruption, highlighted by MRI and gadolinium-induced contrast enhancement in patients, is a common feature of many CNS lesions. This observation suggests an opened paracellular route (between adjacent endothelial cells) and a locally increased BBB permeation of small molecules. Physical BBB disruption may thus be hypothesized to overwhelm the ABCB1/ABCG2-mediated efflux at the BBB. The impact of physical BBB disruption on the ABCB1/ABCG2 function and further brain exposure to erlotinib remain to be elucidated. Methods: The brain kinetics of erlotinib was studied using ¹¹C-erlotinib PET imaging in rats. Physical BBB disruption was achieved using a protocol based on focused ultrasound (FUS) combined with microbubbles, allowing for a large and spatially controlled disruption of the BBB in the left hemisphere. ABCB1/ABCG2 inhibition was performed using i.v elacridar (10 mg/kg), a potent ABCB1/ABCG2 inhibitor. The brain kinetics was studied in 4 groups (n=5 animals per group) including control, FUS only (FUS), elacridar only (ELA) and their combination (FUS+ELA). After PET acquisition, BBB integrity was assessed ex vivo using the Evan's Blue (EB) extravasation test. The brain exposure to ¹¹C-erlotinib was estimated in each hemisphere as the area under the time-activity curve (AUC) from 0 to 30 min of the brain kinetics (% injected dose (%ID) versus time (min)) of ¹¹C-erlotinib in volumes of interest corresponding to the disrupted (left) and the intact (right) hemispheres, respectively. Statistical comparison was performed using a 2-way ANOVA with condition and hemisphere as factors. Results: EB extravasation displayed the substantial BBB disruption in the left hemisphere of animals of the FUS and FUS+ELA groups but not in the control and ELA groups. Compared with baseline (AUC_Baseline = 1.4 ± 0.5 %ID.min), elacridar significantly increased ¹¹C-erlotinib brain exposure to the left hemisphere (AUCELA = 2.2±0.5 %ID.min, p≤0.001). In the presence of a BBB disruption, the effect of elacridar was similar: AUCFUS+ELA was significantly higher (p≤0.001) than AUCFUS (2.1±0.5 %ID.min versus 1.2 0.1 %ID.min, respectively). This confirmed the ABCB1/ABCG2 substrate property of erlotinib at the BBB. Physical BBB disruption did not impact the brain kinetics of ¹¹C-erlotinib in the left hemisphere compared with the control group. AUCleft was never significantly different than AUCright in any of the tested conditions (p≥0.05). Conclusions: Using ¹¹C-erlotinib PET imaging, we showed that ABC-transporter efflux at the BBB may not depend on BBB integrity. The efflux of ABCB1/ABCG2 substrates like erlotinib may persist even when the BBB is physically disrupted. The absence of additional or synergistic effect between ABCB1/ABCG2 inhibition and BBB disruption confirms that ABC-transporter function is the major determinant of erlotinib brain kinetics, thus highlighting the predominance of the 'functional' component barrier rather than the 'physical' component in controlling the brain penetration of this compound. Therefore, FUS-induced BBB disruption is not a relevant strategy to transiently overcome ABC-transporter efflux at the BBB so as to improve the brain delivery of erlotinib and/or to locally potentiate the brain exposure, even in the presence of ABCB1/ABCG2 inhibition

[en] Complete text of publication follows: Objectives Metoclopramide is a widely prescribed antiemetic drug which suffers from rare but severe adverse effects in the central nervous system under prolonged administration. The potential impact of transporter function at the liver level on the metabolism of this P-glycoprotein (ABCB1) substrate and subsequent pharmacokinetics (PK) has not been investigated so far. To that purpose, positon emission tomography (PET) imaging using carbon-11 labeled metoclopramide is an appealing approach to quantify the impact of membrane transporters on drug distribution. Methods O-desmethyl metoclopramide precursor was synthesized in one step from metoclopramide and isotopic labeling with carbon-11 was realized at the methoxy moiety. [¹¹C]Metoclopramide microPET scans were performed on rodents using tracer doses (39.4 MBq; 3.9 μg/kg) or pharmacological doses (36.7 MBq; 3 mg/kg) of metoclopramide with (n=5) or without (n=4) ABCB1 inhibition with tariquidar (8 mg/kg). Liver exposure was estimated using the area under the time-activity curve from 0 to 30 min (AUC, SUV.min). [¹¹C]metoclopramide uptake clearance (Cl_uptake: mL.min^-1.cm^-3 ) was calculated in the liver using the integration plot analysis from 0 to 2 min. [¹¹C]Metoclopramide metabolism and plasma kinetics was studied using radio-HPLC analysis. Results AUC was lower using pharmacological dose (49.2 ± 13.8) compared to tracer dose (210.0 ± 32.4). ABCB1 inhibition enhanced liver AUC with the pharmacological dose (81.0 ± 3.1) but not with the tracer dose (162.0 ± 41.0). Metoclopramide Cl_uptake by the liver was lower using pharmacological dose (0.31 ± 0.23) than tracer dose (0.95 ± 0.24), suggesting a saturable uptake transport. ABCB1 inhibition did not impact [¹¹C]metoclopramide uptake clearance in both pharmacological dose and tracer dose (0.35 ± 0.23 and 1.13 ± 0.48 respectively). Pharmacological dose improved [¹¹C]metoclopramide recovery in plasma (AUCplasma = 8.0 ± 0.02; parent [¹¹C]metoclopramide at 30 min = 40.9 ± 9.1 %) compared to the tracer dose (AUCplasma = 3.8 ± 0.06; parent [¹¹C]metoclopramide at 30 min = 16.7 ± 5.4 %). Conclusions This pharmacological imaging strategy highlighted a saturable transport process at the hepatocyte level which cannot be attributed to ABCB1 function. This carrier-mediated uptake may account for metoclopramide PK variability and tolerance in patients apart from metabolic enzyme intrinsic activity

[en] Complete text of publication follows: Objectives: Buprenorphine (BUP) is an opioid drug used for analgesia and oral substitution for heroin addiction. BUP is metabolized by cytochrome P450 3A4 (CYP3A4) into nor-buprenorphine (nor-BUP), a respiratory depressor accounting for the lethal side effects of BUP.1 To date, poorly is known about the mechanism through which nor-BUP exerts its respiratory effects since in vitro data demonstrated that P-glycoprotein (P-gp, ABCB1) limits its brain penetration. The most advance technique to elucidate the neurokinetic of nor-BUP in vivo is positron emission tomography (PET) imaging using carbon-11 radiolabeled nor-BUP. BUP has already been labeled with carbon-112 but because of the complexity of the related chemistry, no precursor is available for nor-BUP radiolabeling. Herein, we described an original radio-biomimetic (RBM) approach to synthesize ¹¹C-nor-BUP by N-dealkylation of ¹¹C-BUP using CYP3A4 human microsomes and the very first PET images of ¹¹C-nor-BUP in the rat brain with and without inhibition of the P-gp transport function. Methods: Biotransformation of BUP into nor-BUP using CYP3A4 was optimized under non-radioactive conditions, and the conversion rate was determined using HPLC with UV detection. ¹¹C-BUP was synthesized according to the literature and incubated with CYP3A4 under predetermined optimized conditions to afford ready-to-inject ¹¹C-nor-BUP after HPLC purification. Radiochemical yields (RCY), radiochemical purity (RCP), and molar activity (MA) were assessed by analytical radio-HPLC. Sprague-Dawley rats (340 ± 130 g, n = 3) were injected i.v. with ¹¹C-nor-BUP (4.97 ± 4.96 MBq) and brain PET images were acquired. PET data are expressed as standardized uptake values (SUV) taking into account animal weight and injected dose. In addition, ¹¹C-nor-BUP PET imaging under P-gp inhibition conditions using tariquidar (10 mg/kg) are ongoing. Results: Up to 32% of conversion of nor-BUP was obtained under optimized conditions (37 C, 20 min, 1.5 mg/mL of CYP3A4 in the presence of cytochrome b5). Longer reaction time resulted in higher conversion but competed with carbon-11 half-life (t_1/2 = 20.4 min). Using the RBM approach, ¹¹C-nor-BUP was synthesized in 2 ± 1% RCY within 80 minutes with RCP > 98% and 90 ± 15 GBq/μmol MA (n = 7). ¹¹C-nor-BUP showed extremely low penetration in the rat brain (SUV₀→16.5 min = 0.16 ± 0.07). Conclusion: A new original biomimetic approach has been developed to synthesize ¹¹C-norBUP, which was not accessible by the classical radiolabeling routes. The very first PET images of this metabolite in rat brain were recorded, demonstrating in vivo that ¹¹C-nor-BUP does not exert its respiratory depressor activity through the interaction with a target located within the brain

[en] Complete text of publication follows: Objectives: The effects of acute alcohol exposure to the central nervous system may not restrict to its interaction with neuronal pathways and may also involve the innate immune system. Studies using Toll-like receptor 4 (TLR4) deficient mice have elucidated the pivotal role of these receptors in the ethanol-induced immune response. Non-invasive methods are thus required to explore the neuroimmune component of alcohol exposure in vivo. In this study, the neuroimmune response to an initial and acute alcohol exposure was investigated using Translocator Protein 18 kDa (TSPO) PET imaging, a marker of glial activation, in adolescent baboons. Methods: A protocol of alcohol exposure, resulting in controlled plasma concentrations (0.7-1.0 g/L) was developed in baboons. Three different alcohol-naive adolescent baboons (8 to 14 kg, 3-4 year old) underwent ¹⁸F-DPA-714 PET experiments before and during alcohol exposure. Displacement experiments with the reference TSPO ligand PK-11195 (1.5 mg.kg^-1 i.v) were performed after 55 min acquisition to unveil the specific binding of ¹⁸F-DPA-714 to the brain. Extent of displacement was calculated as the percentage change in brain radioactivity before (50 min) and after (75 min) displacement. Each animals underwent a third ¹⁸F-DPA-714 PET experiment 7 to 12 months after alcohol exposure to address its long-term effects. In each experiment, the brain distribution of ¹⁸F-DPA-714 (VT; in mL.cm^-3) was estimated before displacement in several brain regions using the Logan Plot analysis and the metabolite-corrected arterial input function. Regional VTs were compared using a two-way ANOVA with condition and 'brain region' as factors. Results: Compared to alcohol-naive animals (VT brain = 3.7 ± 0.7 mL.cm^-3), the regional VTs of ¹⁸F-DPA-714 were significantly increased during alcohol exposure (VT brain = 7.2 ± 0.4 mL.cm^-3; p≤0.001). Increase in ¹⁸F-DPA-714 binding was not significantly different among brain regions and was shown to be reversible thanks to displacement experiments, indicating specific binding to TSPO. During alcohol exposure, the extent of displacement ranged from 21 to 33 %) and was not significantly different among brain regions (p≥0.05). The regional VTs estimated several months after alcohol exposure (VT brain = 5.7 ± 1.4 mL.cm^-3) were lower (p≤0.001) than those measured during alcohol exposure, but remained significantly higher (p≤0.001) than in alcohol-naive animals. The acute and long-term effects of ethanol exposure on VT were observed globally across all brain regions. Conclusion: Using a nonhuman primate model of alcohol exposure that reflects the 'binge drinking' situation in adolescent individuals, we found that acute alcohol exposure immediately increased the specific binding of ¹⁸F-DPA-714 to the brain compared to alcohol-naive animals. The effect persisted for several months, suggesting a long-term impact of alcohol exposure on glial cell function. ¹⁸F-DPA-714 PET imaging may be useful to non-invasively study the neuroimmune component of alcohol exposure and its involvement in brain function, development and alcohol use disorders

[en] Organic anion-transporting polypeptides (OATPs) mediate the uptake of various drugs from blood into the liver in the basolateral membrane of hepatocytes. Positron emission tomography (PET) is a potentially powerful tool to assess the activity of hepatic OATPs in vivo, but its utility critically depends on the availability of transporter-selective probe substrates. We have shown before that among the three OATPs expressed in hepatocytes (OATP1B1, OATP1B3, and OATP2B1), [C-11]erlotinib is selectively transported by OATP2B1. In contrast to OATP1B1 and OATP1B3, OATP2B1 has not been thoroughly explored yet, and no specific probe substrates are currently available. To assess if the prototypical OATP inhibitor rifampicin can inhibit liver uptake of [C-11]erlotinib in vivo, we performed [C-11]erlotinib PET scans in six healthy volunteers without and with intravenous pretreatment with rifampicin (600 mg). In addition, FVB mice underwent [C-11]erlotinib PET scans without and with concurrent intravenous infusion of high-dose rifampicin (100 mg/kg). Rifampicin caused a moderate reduction in the liver distribution of [C-11]erlotinib in humans, while a more pronounced effect of rifampicin was observed in mice, in which rifampicin plasma concentrations were higher than in humans. In vitro uptake experiments in an OATP2B1-overexpressing cell line indicated that rifampicin inhibited OATP2B1 transport of [C-11]erlotinib in a concentration-dependent manner with a half-maximum inhibitory concentration of 72.0 ± 1.4 mu M. Our results suggest that rifampicin-inhibitable uptake transporter(s) contributed to the liver distribution of [C-11]erlotinib in humans and mice and that [C-11]erlotinib PET in combination with rifampicin may be used to measure the activity of this/these uptake transporter(s) in vivo. Furthermore, our data suggest that a standard clinical dose of rifampicin may exert in vivo a moderate inhibitory effect on hepatic OATP2B1. (authors)

[en] PET with avid substrates of P-glycoprotein (ABCB1) provided evidence of the role of this efflux transporter in effectively restricting the brain penetration of its substrates across the human blood-brain barrier (BBB). This may not reflect the situation for weak ABCB1 substrates including several antidepressants, antiepileptic drugs, and neuroleptics, which exert central nervous system effects despite being transported by ABCB1. We performed PET with the weak ABCB1 substrate C-11-metoclopramide in humans to elucidate the impact of ABCB1 function on its brain kinetics. Methods: Ten healthy male subjects underwent 2 consecutive C-11-metoclopramide PET scans without and with ABCB1 inhibition using cyclosporine A (CsA). Pharmacokinetic modeling was performed to estimate the total volume of distribution (V-T) and the influx (K-1) and efflux (k(2)) rate constants between plasma and selected brain regions. Furthermore, C-11-metoclopramide washout from the brain was estimated by determining the elimination slope (k(E, brain)) of the brain time-activity curves. Results: In baseline scans, C-11-metoclopramide showed appreciable brain distribution (V-T = 2.11 ± 0.33 mL/cm(3)). During CsA infusion, whole-brain gray matter V-T and K-1 were increased by 29% ± 17% and 9% ± 12%, respectively. K-2 was decreased by 15% ± 5%, consistent with a decrease in k(E, brain) (-32% ± 18%). The impact of CsA on outcome parameters was significant and similar across brain regions except for the pituitary gland, which is not protected by the BBB. Conclusion: Our results show for the first time that ABCB1 does not solely account for the 'barrier' property of the BBB but also acts as a detoxifying system to limit the overall brain exposure to its substrates at the human blood-brain interface. (authors)

[en] Complete text of publication follows: Objectives: The parameters that control the variability of response and tolerance to opioid analgesics are not fully understood. Many preclinical studies have highlighted the interaction of morphine and other opioids with the innate immune system of the brain, especially microglial cells. Morphine was shown to promote microglial activation and trigger inflammatory pathways such as that of Toll-like receptor 4 (TLR4), with the release of pro-inflammatory cytokines in the brain. Interestingly, morphine-induced microglial activation was shown to modulate its pain-relieving properties. This suggests that glial modulation may be an underexplored parameter of the variability of response to opioids in patients. The relevance of Translocator protein 18 kDa (TSPO) PET imaging with ¹⁸F-DPA-714, a marker of glial activation, was investigated as a minimally-invasive method to investigate morphine-induced glial activation in vivo. Methods: Five Male Papio anubis baboons (25-30 kg, 8-10 years old) underwent ¹⁸F-DPA-714 PET imaging (226 ± 21 MBq - 120 min dynamic PET acquisition, HR+ Siemens scanner) at baseline and 2 hours after intramuscular morphine injection (1 mg/kg). Brain kinetics and metabolite-corrected input function were measured to estimate ¹⁸F-DPA-714 brain distribution in the whole brain and in 12 brain regions (VT; mL.cm^-3; Logan graphical analysis). Brain VTs obtained in the presence or in the absence of morphine were statistically compared by a paired t-test. Response to morphine administration was characterized by the ratio R of VT after morphine injection over VT before morphine injection. Results: Morphine did not influence the plasma kinetics of ¹⁸F-DPA-714, indicating the absence of peripheral drug-drug interaction between these compounds: parent ¹⁸F-DPA-714 in plasma, measured from 40 to 120 min (elimination phase) were not different between baseline (SUV = 0.06 ± 0.01) and acute morphine conditions (SUV = 0.05 ± 0.01). In morphine-treated animals, ¹⁸F-DPA-714 VT was significantly higher than VT at baseline (18.8 ± 11.8 mL.cm^-3 vs 14.3 ± 8.4 mL.cm^-3, p≤0.05). Regional analysis and ANOVA showed that the response to morphine as measured by R was not significantly different (p≥0.05) between the different brain regions. High differences in the basal distribution of ¹⁸F-DPA-714 were observed among the baboons. We did not identify any parameter (origin, age, nature/number of previous anesthesia or treatments) that could explain this disparity. Interestingly, the response to morphine exposure predominated in animals with a higher baseline distribution. Conclusion: Acute morphine exposure significantly increases the binding of ¹⁸F-DPA-714 to the brain in nonhuman primates. The effect was observed globally across brain regions and predominated in animals with the highest baseline uptake, suggesting that priming parameters still to be identified play a role in controlling the neuroimmune response to morphine. PET imaging using ¹⁸F-DPA-714 is a relevant approach for the minimally-invasive study of the neuroimmune component of morphine pharmacology in vivo

[en] Drugs promoting myelin repair represent a promising therapeutic approach in multiple sclerosis and several candidate molecules are currently being evaluated, fostering the need of a quantitative method to specifically measure myelin content in vivo. PET using the benzothiazole derivative ${}^{11}$C-PiB has been successfully used to quantify myelin content changes in humans. Stilbene derivatives, such as ${}^{11}$C-MeDAS, have also been shown to bind to myelin in animals and are considered a promising radiopharmaceutical class for myelin imaging. Fluorinated compounds from both classes are now commercially available and thus should constitute clinically useful myelin radiotracers. The aim of this study is to provide a head-to-head comparison of ${}^{18}$F-florbetaben, ${}^{18}$F-florbetapir, ${}^{18}$F-flutemetamol, ${}^{11}$C-MeDAS, and ${}^{11}$C-PiB with regard to brain kinetics and binding in white matter (WM). Four baboons underwent a 90-min dynamic PET scan for each radioligand. Arterial blood samples were collected during the exam for each radiotracer, except for ${}^{18}$F-florbetapir, to obtain a radiometabolite-corrected input function. Standardized uptake value ratio between 75 at 90 min (SUVR${}_{75\text{â<!-- ?? -->}\text{€<!-- ??? -->}\text{“<!-- ??? -->}90}$), binding potential (BP) estimated with Logan method with input function, and distribution volume ratio (DVR) estimated with Logan reference method (using cerebellar gray matter as reference region) were calculated in WM and compared between tracers using mixed effect models. In WM, ${}^{18}$F-florbetapir had the highest SUVR${}_{75\text{â<!-- ?? -->}\text{€<!-- ??? -->}\text{“<!-- ??? -->}90}$ (1.38 ± 0.03), followed by ${}^{18}$F-flutemetamol (1.34 ± 0.02), ${}^{18}$F-florbetaben (1.32 ± 0.07), ${}^{11}$C-MeDAS (1.27 ± 0.04), and ${}^{11}$C-PiB (1.25 ± 0.07). With regard to BP, ${}^{18}$F-florbetaben had the highest value (0.32 ± 0.06) compared with ${}^{18}$F-flutemetamol (0.20 ± 0.03), ${}^{11}$C-MeDAS (0.17 ± 0.03), and ${}^{11}$C-PiB (0.16 ± 0.03). No difference in DVR was detected between ${}^{18}$F-florbetaben (1.26 ± 0.06) and ${}^{18}$F-florbetapir (1.27 ± 0.03), but both were significantly higher in DVR than ${}^{18}$F-flutemetamol (1.17 ± 0.02), ${}^{11}$C-MeDAS (1.16 ± 0.03), and ${}^{11}$C-PiB (1.14 ± 0.02). Given their higher binding and longer half-life, our study indicates that ${}^{18}$F-florbetapir and 18F-florbetaben are promising tracers for myelin imaging which are readily available for clinical application in demyelinating diseases.

[en] Complete text of publication follows: Introduction: Multiple sclerosis (MS) is the most common demyelinating disease in human, affecting more than 2 million people worldwide. Drugs promoting myelin repair represent a promising therapeutic approach and several molecules are currently being evaluated. A reliable imaging method to specifically quantify myelin in vivo is crucially needed to test the efficacy of these drugs. Positron emission tomography (PET) using the benzothiazole derivative ¹¹C-PiB, repurposed as a myelin biomarker, has been successfully used to quantify myelin content changes in humans, but it is characterized by a suboptimal signal-to-noise ratio. Another promising class of radiopharmaceutical compounds is the family of stilbene derivatives, such as ¹¹C-BMB and ¹¹C-MeDAS, which have been shown to bind to myelin in animal models. Fluorinated analogues ¹⁸F-florbetapir and ¹⁸F-florbetaben, belonging to these chemical classes, are now commercially available and may offer clinically useful radiotracers for myelin imaging. Objectives: This study aimed to compare ¹¹C-MeDAS, ¹⁸F-florbetapir and ¹⁸F-florbetaben with ¹¹C-PiB, with regard to brain kinetic properties and discriminative potential between white (WM) and grey matter (GM) binding. Methods: Four healthy baboons (27.2 ± 2.3 kg) were included in the study and underwent a PET scan for each radioligand, with a minimum rest period of 2 weeks. Dynamic cerebral PET scans were acquired during 90 minutes under propofol anesthesia after radiotracer injection (244.6 ±.37.8 MBq). The brain kinetic of each radiotracer, expressed as standardized uptake values (SUV), were evaluated in terms of (1) radioligand uptake in the WM, (2) binding ratio of WM over GM (ratio WM/GM) and (3) stability of the ratio WM/GM over the scan duration. Results: The brain distribution was comparable across the four radiotracers, with a greater uptake in the WM compared to the GM. (1) The WM uptake of ¹⁸F-florbetaben (SUV_90min = 1.72 ± 0.10) was higher than that of ¹¹C-MeDAS (SUV_90min = 1.68 ± 0.20), ¹⁸F-florbetapir (SUV_90min = 1.47 ± 0.20) and ¹¹C-PiB (SUV_90min = 0.46 ± 0.05). (2) Ratio WM/GM measured at 90 minutes post-injection of ¹⁸F-florbetapir (1.28 ± 0.03) and ¹⁸F-florbetaben (1.25 ± 0.04), were higher than that of ¹¹C-MeDAS (1.19 ± 0.02) and ¹¹C-PiB (1.17 ± 0.04). (3) The ratio WM/GM reached an equilibrium at 50 minutes post injection for ¹¹C-PiB, but this equilibrium was not reached over the PET exam for the other tested radiotracers. Conclusions: All the stilbene derivatives showed a higher WM uptake and ratio WM/GM, compared to ¹¹C-PiB, which supports their use as alternative myelin PET tracers. Fluorinated radiotracers showed higher ratio WM/GM compared with carbon-11 radiolabelled ones. Only ¹¹C-PiB reached a stable ratio WM/GM over the PET scan duration