Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase

Liu, Ping; Hamill, Terence G.; Chioda, Marc; Chobanian, Harry R.; Fung, Selena; Guo, Yan; Chang, Linda; Bakshi, Raman K.; Hong, Qingmei; Dellureficio, James; Lin, Linus S.; Abbadie, Catherine; Alexander, Jessica P.; Jin, Hong; Mandala, Suzanne; Shiao, Lin‐Lin; Sanabria, Sandra; Williams, David L.; Zeng, Zhizhen; Hajdu, Richard; Jochnowitz, Nina; Rosenbach, Mark; Karanam, Bindhu V.; Madeira, Maria; Salituro, Gino; Powell, Joyce; Xu, Ling; Terebetski, Jenna L.; Leone, Joseph F.; Miller, Patricia; Cook, Jacquelynn J.; Holahan, Marie A.; Joshi, Aniket; O’Malley, Stacey; Purcell, Mona; Posavec, Diane; Chen, Tsing-Bau; Riffel, Kerry; Williams, M. A.; Hargreaves, Richard; Sullivan, Kathleen; Nargund, Ravi P.; DeVita, Robert J.

doi:10.1021/ml4000996

Cited by 34 publications

(45 citation statements)

References 27 publications

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“…The tissue response function in brain was measured from the PET images. PET scans were acquired on a HiRez Biograph 16 slice PET/CT camera (Siemens, Erlangen, Germany) with [ 11 C]MK3168 tracer produced as previously described 6. A slow bolus injection (356 ± 57MBq; molar activity 111 ± 67 GBq/μmol) of [ 11 C]MK3168 was synchronized with the start of a 90‐min list‐mode acquisition.…”

Section: Methodsmentioning

confidence: 99%

Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers

Postnov

Schmidt

Pemberton

et al. 2018

Clinical Translational Sci

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Inhibition of fatty acid amide hydrolase (FAAH) potentiates endocannabinoid activity and is hypothesized to have therapeutic potential for mood and anxiety disorders and pain. The clinical profile of JNJ‐42165279, an oral selective FAAH inhibitor, was assessed by investigating the pharmacokinetics, pharmacodynamics, safety, and binding to FAAH in the brain of healthy human volunteers. Concentrations of JNJ‐42165279 (plasma, cerebrospinal fluid (CSF), urine) and fatty acid amides (FAA; plasma, CSF), and FAAH activity in leukocytes was determined in a phase I multiple ascending dose study. A positron emission tomography study with the FAAH tracer [11C]MK3168 was conducted to determine brain FAAH occupancy after single and multiple doses of JNJ‐42165279. JNJ‐42165279 administration resulted in an increase in plasma and CSF FAA. Significant blocking of brain FAAH binding of [11C]MK3168 was observed after pretreatment with JNJ‐42165279. JNJ‐42165279 produces potent central and peripheral FAAH inhibition. Saturation of brain FAAH occupancy occurred with doses ≥10 mg of JNJ‐42165279. No safety concerns were identified.

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Section: Methodsmentioning

confidence: 99%

Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers

Postnov

Schmidt

Pemberton

et al. 2018

Clinical Translational Sci

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“…110 The exploration was based on a lead compound 78 ( Figure 33), which was previously identified as a potent FAAH inhibitor. 110 However, compound 78 possessed an unfavorable lipophilicity (LogD = 4.2 at pH 7.3) complicating the in vivo PET studies in rhesus monkeys. To optimize lipophilicity and brain penetration, several modifications were performed.…”

Section: Arylthioheterocyclesmentioning

confidence: 99%

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

et al. 2016

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“…Receptor concentrations in rats and humans were used interchangeably since no complete set of receptor densities could be obtained for either rats or humans. Values found in literature have shown to differ no more than tenfold (41,45 (42,46). The receptor density in the hypothalamus in femtomole/ milligram was divided by the receptor density in nanogram/ milligram lysate, and the resulting coefficient was used to transform the receptor density in nanogram/milligram lysate of the cerebellum, hypothalamus, and frontal cortex to the corresponding receptor density in femtomole/milligram.…”

Section: Parametersmentioning

confidence: 99%

Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling

Vlot

Witte

Danhof

et al. 2017

AAPS J

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Abstract.Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D ) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ 8 -tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokineticpharmacodynamic modeling provides an improved understanding of tissue and target selectivity.

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Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase

Cited by 34 publications

References 27 publications

Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers

Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling

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