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394. Development and Preclinical Evaluation of [18F]JNJ-64413739 as a PET Radioligand for P2X7 Receptors
Biological Psychiatry
Friday Abstracts
Conclusions: Those at genetic risk with MDD demonstrated aberrant hippocampal activation during an emotional memory task. This was potentially driven by a lack of insula’s inhibitory influence between sensory cortex and amygdala, which in turn directly influenced hippocampal activation. Supported By: Wellcome Trust; Royal College of Physicians of Edinburgh; Health Foundation; NARSAD; Scottish Funding Council; NHS Research Scotland; Sackler Foundation; European Union's Seventh Framework Programme Keywords: Emotional Memory, familial risk, longitudinal cohort, Mood disorders, Dynamical Causal Modeling
394. Development and Preclinical Evaluation of [18F]JNJ64413739 as a PET Radioligand for P2X7 Receptors Hartmuth Kolb1, Wei Zhang2, Gang Chen2, Chunfang Xia2, Katrin Szardenings2, Anindya Bhattacharya2, Brian Lord2, Michael Letavic2, and Jose I. Andres3 1 2
Johnson & Johnson / Janssen Research & Development, Janssen R&D, 3Janssen
Background: The P2X7 receptor is an adenosine triphosphate (ATP)-gated ion-channel. P2X7R activation leads to the release of the pro-inflammatory cytokine IL-1b in the brain and as such the P2X7 receptor may play a role in neuroinflammation. Herein we describe the development of [18F]JNJ-64413739, a 18Flabelled PET ligand for imaging the P2X7 receptor. Methods: The P2X7R affinity and specificity, pharmacokinetics, metabolic stability, BBB permeability, and off-target binding of JNJ-64413739 were evaluated. The labeled radiotracer [18F]JNJ64413739 was synthesized by nucleophilic aromatic substitution. The specific binding of [18F]JNJ-64413739 was evaluated through a series of in vitro autoradiography (ARG) experiments with rodent brain tissue sections. The P2X7R PET tracer was also studied in rhesus macaques. Results: The potency of JNJ-64413739 is 1.9 nM and 1.0 nM at the recombinant rat and human P2X7 receptor (IC50s, FLIPR), respectively, and the binding affinity is 2.7 nM (Ki, rat cortex binding assay) and 15 nM (Ki, human P2X7r). In vitro ARG blocking experiments with [18F]JNJ-64413739 demonstrated inhibition of tracer binding to rat brain tissue sections in a dosedependent manner by two P2X7R antagonists. Non-human primate PET imaging studies (two rhesus monkeys) revealed dose-dependent receptor occupancy (RO) of JNJ-54175446. Conclusions: JNJ-64413739 is a potent and selective ligand for rat and human P2X7R. In vitro ARG experiments with hP2X7R rats and WT/KO mice brain sections suggested that [18F]JNJ64413739 engaged the P2X7 receptor. Reproducible and dosedependent RO of JNJ-54175446 was obtained in rhesus monkeys by PET imaging with [18F]JNJ-64413739. This PET tracer exhibits characteristics suitable for imaging the P2X7 receptor. Keywords: Neuroinflammation, Positron Emission Tomography, P2X7R, Radiotracer
395. Anterior Cingulate Cortex Morphology Predicts Treatment Response to Internet-Based CBT for Depression Christian Webb1, Elizabeth Olson1, William D.S. Killgore2, Diego Pizzagalli1, Scott Rauch1, and Isabelle Rosso1
Harvard Medical School and McLean Hospital, 2University of Arizona 1
Background: Rostral anterior cingulate cortex (rACC) activity has been shown to predict depressive symptom improvement across different antidepressant treatments. This study extends prior work by examining whether rACC morphology predicted treatment response to internet-based cognitive behavioral therapy (iCBT) for major depressive disorder (MDD). Methods: Hierarchical linear modeling (HLM) tested whether pre-treatment rACC volume predicted self-reported (Patient Health Questionnaire–9; PHQ-9) depressive symptom improvement during a 10-week randomized clinical trial of iCBT (n 5 37) vs. a monitored attention control (MAC; n 5 40). We also tested whether pre-treatment rACC volumes differed between depression remitters vs. non-remitters (using the Hamilton Rating Scale for Depression; HRSD). The PHQ-9 was completed 8 times over the course of treatment; whereas the HRSD was administered at pre- and post-treatment. Results: Larger right (F[1,32.2] 5 8.47, p , 0.01), but not left (F [1,32.9] 5 0.56, p50.46), rACC volume was a significant predictor of greater PHQ-9 symptom improvement in iCBT, even when controlling for demographic (age, gender, race) and clinical (baseline depression, anhedonia and anxiety) variables previously linked to treatment response. In addition, pretreatment right (F(1,16) 5 6.01, p50.03), but not left (F(1,16) 5 0.31, p50.59), rACC volume was larger among iCBT patients whose depression remitted relative to those who did not remit. Corresponding analyses in the MAC group were not significant. Conclusions: For MDD patients, rACC volume prior to iCBT demonstrated incremental predictive validity beyond clinical and demographic variables previously found to predict symptom improvement. If replicated, such morphological measures could be integrated into clinical care to inform treatment decisionmaking. Supported By: USAMRAA Award W81XWHC12C0109 (Rauch); NIMH K23 MH108752 (Webb); NIMH R01: MH096987 (Rosso) Keywords: Anterior Cingulate Cortex, Prediction of Treatment Outcome, Internet, Cognitive Behavior Therapy, Randomized controlled trial
ORAL SESSION Clinical/Translational Neuroscience of Psychosis and Related Disorders - #2 Friday, May 19, 2017 - 3:00 PM - 5:00 PM Aqua 300 AB Chair: Erica Duncan 396. Neuroplasticity Benefits of Adding Aerobic Exercise to Cognitive Training in First-Episode Schizophrenia Patients Sarah McEwen, Behnaz Jarrahi, Kenneth Subotnik, Joseph Ventura, and Keith Nuechterlein UCLA Department of Psychiatry & Biobehavioral Sciences
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal
S161
Friday Abstracts
Conclusions: Those at genetic risk with MDD demonstrated aberrant hippocampal activation during an emotional memory task. This was potentially driven by a lack of insula’s inhibitory influence between sensory cortex and amygdala, which in turn directly influenced hippocampal activation. Supported By: Wellcome Trust; Royal College of Physicians of Edinburgh; Health Foundation; NARSAD; Scottish Funding Council; NHS Research Scotland; Sackler Foundation; European Union's Seventh Framework Programme Keywords: Emotional Memory, familial risk, longitudinal cohort, Mood disorders, Dynamical Causal Modeling
394. Development and Preclinical Evaluation of [18F]JNJ64413739 as a PET Radioligand for P2X7 Receptors Hartmuth Kolb1, Wei Zhang2, Gang Chen2, Chunfang Xia2, Katrin Szardenings2, Anindya Bhattacharya2, Brian Lord2, Michael Letavic2, and Jose I. Andres3 1 2
Johnson & Johnson / Janssen Research & Development, Janssen R&D, 3Janssen
Background: The P2X7 receptor is an adenosine triphosphate (ATP)-gated ion-channel. P2X7R activation leads to the release of the pro-inflammatory cytokine IL-1b in the brain and as such the P2X7 receptor may play a role in neuroinflammation. Herein we describe the development of [18F]JNJ-64413739, a 18Flabelled PET ligand for imaging the P2X7 receptor. Methods: The P2X7R affinity and specificity, pharmacokinetics, metabolic stability, BBB permeability, and off-target binding of JNJ-64413739 were evaluated. The labeled radiotracer [18F]JNJ64413739 was synthesized by nucleophilic aromatic substitution. The specific binding of [18F]JNJ-64413739 was evaluated through a series of in vitro autoradiography (ARG) experiments with rodent brain tissue sections. The P2X7R PET tracer was also studied in rhesus macaques. Results: The potency of JNJ-64413739 is 1.9 nM and 1.0 nM at the recombinant rat and human P2X7 receptor (IC50s, FLIPR), respectively, and the binding affinity is 2.7 nM (Ki, rat cortex binding assay) and 15 nM (Ki, human P2X7r). In vitro ARG blocking experiments with [18F]JNJ-64413739 demonstrated inhibition of tracer binding to rat brain tissue sections in a dosedependent manner by two P2X7R antagonists. Non-human primate PET imaging studies (two rhesus monkeys) revealed dose-dependent receptor occupancy (RO) of JNJ-54175446. Conclusions: JNJ-64413739 is a potent and selective ligand for rat and human P2X7R. In vitro ARG experiments with hP2X7R rats and WT/KO mice brain sections suggested that [18F]JNJ64413739 engaged the P2X7 receptor. Reproducible and dosedependent RO of JNJ-54175446 was obtained in rhesus monkeys by PET imaging with [18F]JNJ-64413739. This PET tracer exhibits characteristics suitable for imaging the P2X7 receptor. Keywords: Neuroinflammation, Positron Emission Tomography, P2X7R, Radiotracer
395. Anterior Cingulate Cortex Morphology Predicts Treatment Response to Internet-Based CBT for Depression Christian Webb1, Elizabeth Olson1, William D.S. Killgore2, Diego Pizzagalli1, Scott Rauch1, and Isabelle Rosso1
Harvard Medical School and McLean Hospital, 2University of Arizona 1
Background: Rostral anterior cingulate cortex (rACC) activity has been shown to predict depressive symptom improvement across different antidepressant treatments. This study extends prior work by examining whether rACC morphology predicted treatment response to internet-based cognitive behavioral therapy (iCBT) for major depressive disorder (MDD). Methods: Hierarchical linear modeling (HLM) tested whether pre-treatment rACC volume predicted self-reported (Patient Health Questionnaire–9; PHQ-9) depressive symptom improvement during a 10-week randomized clinical trial of iCBT (n 5 37) vs. a monitored attention control (MAC; n 5 40). We also tested whether pre-treatment rACC volumes differed between depression remitters vs. non-remitters (using the Hamilton Rating Scale for Depression; HRSD). The PHQ-9 was completed 8 times over the course of treatment; whereas the HRSD was administered at pre- and post-treatment. Results: Larger right (F[1,32.2] 5 8.47, p , 0.01), but not left (F [1,32.9] 5 0.56, p50.46), rACC volume was a significant predictor of greater PHQ-9 symptom improvement in iCBT, even when controlling for demographic (age, gender, race) and clinical (baseline depression, anhedonia and anxiety) variables previously linked to treatment response. In addition, pretreatment right (F(1,16) 5 6.01, p50.03), but not left (F(1,16) 5 0.31, p50.59), rACC volume was larger among iCBT patients whose depression remitted relative to those who did not remit. Corresponding analyses in the MAC group were not significant. Conclusions: For MDD patients, rACC volume prior to iCBT demonstrated incremental predictive validity beyond clinical and demographic variables previously found to predict symptom improvement. If replicated, such morphological measures could be integrated into clinical care to inform treatment decisionmaking. Supported By: USAMRAA Award W81XWHC12C0109 (Rauch); NIMH K23 MH108752 (Webb); NIMH R01: MH096987 (Rosso) Keywords: Anterior Cingulate Cortex, Prediction of Treatment Outcome, Internet, Cognitive Behavior Therapy, Randomized controlled trial
ORAL SESSION Clinical/Translational Neuroscience of Psychosis and Related Disorders - #2 Friday, May 19, 2017 - 3:00 PM - 5:00 PM Aqua 300 AB Chair: Erica Duncan 396. Neuroplasticity Benefits of Adding Aerobic Exercise to Cognitive Training in First-Episode Schizophrenia Patients Sarah McEwen, Behnaz Jarrahi, Kenneth Subotnik, Joseph Ventura, and Keith Nuechterlein UCLA Department of Psychiatry & Biobehavioral Sciences
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal
S161