- Email: [email protected]
P.1.i.002 Subgenual anterior cingulate cortical functional connectivity in treatment-resistant depression
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P.1.i. Basic and clinical neuroscience − Brain imaging and neuro-modulation
P.1.i. Basic and clinical neuroscience − Brain imaging and neuro-modulation P.1.i.001 Dopamine D2/3 receptor availability and human cognitive impulsivity: a high-resolution PET imaging study with [11 C]raclopride J.H. Kim1 ° , Y.D. Son2 , S.Y. Lee2 , Y.B. Kim3 , Z.H. Cho3 1 Gachon University Gil Medical Center, Department of Psychiatry, Incheon, South-Korea; 2 Gachon University, Neuroscience Research Institute, Incheon, South-Korea; 3 Gachon University, Neurosurgery Neuroscience Research Institute, Incheon, South-Korea Purpose of the study: Human impulsivity is a complex multidimensional construct encompassing cognitive, emotional, and behavioral aspects. Previous animal studies have suggested that striatal dopamine receptors play a critical role in impulsivity [1]. In this study, we investigated the relationship between self-reported impulsiveness and dopamine D2/ 3 receptor availability in striatal subdivisions in healthy subjects using high-resolution positron emission tomography (PET) with [11 C]raclopride. Methods: Twenty-one healthy normal subjects (8 men, 13 women; mean age: 34.6±8.8 years; mean years of education: 14.8±1.5) participated in the study after giving their written informed consent. All subjects completed PET scanning using the High-Resolution Research Tomograph (HRRT) system (Siemens Molecular Imaging, Knoxville, TN). Emission data were collected as listmode data in the 3-dimensional mode during the 60 minutes after [11 C]raclopride injection. The tracer [11 C]raclopride was synthesized by methylation of the desmethyl precursor using [11 C]iodomethane. To achieve accurate delineation of the brain regions for data analysis, each subject underwent a magnetic resonance imaging (MRI) scan using a 3-Tesla scanner (Magnetom Verio; Siemens, Germany). The MRI scan of each subject was coregistered to his or her PET scan using statistical parameter mapping software (SPM8). Regions of interest (ROIs) were drawn on each individual’s MRI. The striatum was divided into 5 anatomic ROIs, such as the ventral striatum (VST), the pre-commissural dorsal caudate (preDCA), the pre-commissural dorsal putamen (preDPU), the post-commissural caudate (postCA), and the post-commissural putamen (postPU), following the guidelines specified in the studies by Mawlawi et al. [2] and Martinez et al. [3]. Time-activity curves were generated for each ROI by averaging the dynamic PET images, which were coregistered to the corresponding MRI images. The distribution volume ratio (DVR) for [11 C]raclopride was obtained on the basis of the Logan graphical method. The trait of impulsiveness was measured using the Barratt Impulsiveness Scale (BIS-11). To control for the potentially confounding effects of general temperament characteristics that are conceptually or empirically related to dopamine, the Temperament and Character Inventory (TCI) was administered for measuring the biogenetic temperament of harm avoidance and novelty seeking. Partial correlation analysis was performed between BIS-11 scores and D2/ 3 receptor availability in striatal subregions, controlling for age and TCI scores. The level of statistical significance was defined as p < 0.05 (two-tailed). Results: The analysis revealed that the non-planning and attentional impulsiveness subscale scores of the BIS-11 had significant positive correlations with the DVR value of [11 C]raclopride in the
preDCA (non-planning: r = 0.65, p = 0.004, attentional: r = 0.61, p = 0.007). There was a tendency toward positive correlation between the non-planning impulsiveness score and the [11 C]raclopride DVR value in the postCA (r = 0.43, p = 0.075). No significant correlations were observed between the motor impulsiveness score and the [11 C]raclopride DVR values in any subregion. Conclusions: These results suggest that cognitive subtrait of impulsivity is associated with D2/ 3 receptor availability in the associative striatum that plays a critical role in cognitive processes involving attention to detail, judgment of alternative outcomes, and inhibitory control. References [1] Dalley, J.W., Fryer, T.D., Brichard, L., Robinson, E.S., Theobald, D.E., L¨aa¨ ne, K., Pe˜na, Y., Murphy, E.R., Shah, Y., Probst, K., Abakumova, I., Aigbirhio, F.I., Richards, H.K., Hong, Y., Baron, J.C., Everitt, B.J., Robbins, T.W., 2007. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315, 1267–1270. [2] Mawlawi, O., Martinez, D., Slifstein, M., Broft, A., Chatterjee, R., Hwang, D.R., Huang, Y., Simpson, N., Ngo, K., Van Heertum, R., Laruelle, M., 2001. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2)receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21, 1034–1057. [3] Martinez, D., Slifstein, M., Broft, A., Mawlawi, O., Hwang, D.R., Huang, Y., Cooper, T., Kegeles, L., Zarahn, E., Abi-Dargham, A., Haber, S.N., Laruelle, M., 2003. Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamineinduced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab 23, 285–300.
P.1.i.002 Subgenual anterior cingulate cortical functional connectivity in treatment-resistant depression C. Baeken1 ° , D. Marinazzo2 , G.R. Wu2 , P. Van Schuerbeek3 , J. De Mey3 , R. De Raedt4 1 Free University of Brussels, Dept of psychiatry, Brussels, Belgium; 2 Ghent University, Department of Data Analysis, Ghent, Belgium; 3 Free University of Brussels, Department of Radiology and Medical Imaging, Brussels, Belgium; 4 Free University of Brussels, Department of Experimental Clinical and Health Psychology, Ghent, Belgium Purpose of the study: Major depression disorder (MDD) is a worldwide mental health problem affecting millions. Unfortunately, not all patients respond to the available pharmacological treatment algorithms and refractory depression is not uncommon. Further, the phenomenon of treatment-resistant depression (TRD) still remains unclear. Because of the pervasive and persistent nature of depressive symptoms, resting-state fMRI has been proposed as a new promising neuroimaging technique to examine alterations of network connectivity in MDD patients at rest. In spite that the subgenual anterior cingulate cortex (sgACC) has consistently been documented to be deregulated in MDD no resting state functional connectivity (rsFC) studies yet focused on sgACC dysfunction in TRD. As it was stated that a stronger FC anti-correlation between the sgACC and distinct parts of the (dorsal) prefrontal cortex (DLPFC) could be indicative for clinical response to repetitive Transcranial Magnetic Stimulation (rTMS) [1], our research objective was to evaluate whether FC sgACC could differentiate high-frequency (HF)-rTMS (non) responders from never-depressed controls at baseline. Methods: We examined 20 antidepressant-free unipolar melancholic TRD patients (at least stage III) (Female:Male [F:M] =
P.1.i. Basic and clinical neuroscience − Brain imaging and neuro-modulation 15:4; mean age 49.4 y, sd 11.1) and 20 never-depressed individuals matched for age and gender (F:M = 15:4; mean age 44.9 y, sd 11.9). TRD patients were tapered-off their psychotropic drugs and all were medication-free for at least two weeks before scanning. Hereafter, only patients followed an intensive sham-controlled HF-rTMS treatment protocol applied to the left DLPFC [2]. Clinical response was defined as a 50% reduction of the baseline Hamilton Depression Rating Scale score. Fisher’s r-to-Z maps were submitted to a random-effect analysis in SPM8 in an independent Ti-test design containing age as covariate, thresholded with Alphasim correction with a cluster extent threshold (K) of 46 voxels and a voxel significance threshold of 0.05. The sgACC MNI coordinates were selected from Cisler [3] defining centroids of nodes comprising an affective cognitive network. Summary of results: Seven patients were identified as clinical responders after real HF-rTMS treatment and no patients responded to sham. Compared to the control group, TRD patients displayed significantly less sgACC FC with the right posterior cingulate gyrus (PCG) and significantly more sgACC FC with the right middle frontal gyrus. Importantly, our data also indicate that these FC sgACC differences seem to be driven by HF-rTMS responders and non-responders. Whereas HF-rTMS responders showed less sgACC FC with the right PCG, non-responders displayed stronger sgACC FC with the right prefrontal cortex. Conclusions: sgACC FC patterns are not univocal across depressed patients documented to be resistant to several pharmacotherapeutic interventions and can further be differentiated when such patients are responsive or not to non-invasive HF-rTMS treatment. Our results confirm the importance of PCG in MDD and the involvement of a continuous deregulation pattern between the sgACC and the right prefrontal cortex in HF-rTMS nonresponders. Our findings provide further insights into the complexity of sgACC deregulated networks and the possible indication for non-invasive neuromodulation options for TRD patients. References [1] Fox, M.D., Buckner, R.L., White, M.P., Greicius, M.D., PascualLeone, A., 2012 Efficacy of Transcranial Magnetic Stimulation Targets for Depression Is Related to Intrinsic Functional Connectivity with the Subgenual Cingulate. Biol Psychiatry 72, 595–603. [2] Zeeuws, D., De Rycker, K., De Raedt, R., De Beyne, M., Baeken, C., Vanderbruggen, N., 2011 Intensive high-frequency repetitive transcranial magnetic stimulation treatment in an electroconvulsive shock therapy-resistant bipolar I patient with mixed episode. Brain Stimul 4, 46−49. [3] Cisler, J.M., James, G.A., Tripathi, S., Mletzko, T., Heim, C., Hu, X.P., Mayberg, H.S., Nemeroff, C.B., Kilts, C.D., 2012 Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress. Psychol Med 10, 1−12.
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P.1.i.003 PET brain imaging of neuropeptide Y2 receptors D. Smith1 ° , M. Winterdahl2 , H. Audrain2 , A. Landau3 , P. Bonaventure4 , J. Shoblock4 , N. Carruthers4 , D. Swanson4 , D. Bender2 1 Aarhus University Hospital, Center for Psychiatric Research, Risskov, Denmark; 2 Aarhus University Hospital, PET Center, Aarhus, Denmark; 3 Aarhus University Hospital, PET Center & CFIN, Aarhus, Denmark; 4 Janssen Pharm, Research & Development, San Diego CA, USA Purpose of the study: Neuropeptide Y2 (NPY2) receptors are implicated in diverse brain disorders, but no suitable PET radiotracers are currently available for studying NPY2 receptors in the living brain. Therefore, we prepared a positron-emitting radioligand based on a novel NPY2 receptor antagonist, JNJ31020028, and used the compound for PET brain imaging in living pigs. In vitro receptor autoradiographic studies were also carried out to establish the anatomical distribution of NPY2 receptors in pig brain. Methods used: Yorkshire × Landrace pigs weighing 35−40 kg were used. Baseline and post-challenge PET recordings of N-[11 C]methyl-JNJ-31020028 in living pig brain were conducted for 90 min, concurrent with arterial blood sampling, and with unlabelled JNJ-31020028 as pharmacologic intervention. Cyclosporin A was used to enhance levels of the PET radiotracer in the brain. The PET images were manually coregistered to an MR atlas of the pig brain. Parametric images of the binding potentials of NPY2 receptors towards the N-[11 C]methyl-JNJ31020028 in the living brain were calculate using the simplified reference tissue method and compared to a three compartment plasma input model. Summary of results containing real data and appropriate statistical assessments: We noted high densities of N-[11 C]methyl-JNJ-31020028 receptor binding sites in autoradiography studies primarily in hippocampus; they were inhibited by unlabeled JNJ-31020028. In PET studies, N-[11 C]-methyl-JNJ31020028 was metabolized slowly in the bloodstream, with 25% of [11 C]-labeled parent compound remaining 30 minutes after injection. A strong linear correlation (r = 0.92; P = 0.01) was found between estimates of binding potentials obtained with a three compartment plasma input model and the simplified reference tissue method. The simplified reference tissue method showed baseline binding potentials of 0.55±0.02 in caudate nucleus, 0.49±0.03 in hippocampus, and 0.34±0.07 in frontal cortex. N-[11 C]methyl-JNJ31020028 binding was reversible, in that infusion of unlabeled JNJ-31020028 markedly displaced the PET radioligand from binding sites in caudate nucleus, hippocampus, and frontal cortex. Conclusions: N-[11 C]methyl-JNJ-31020028 is the first candidate radioligand with suitable properties for PET imaging of NPY2 receptors in the living brain. Firstly, it is metabolized slowly in the bloodstream, according to our studies in pigs. Secondly, using cyclosporin, the target-to-background ratio of N-[11 C]methylJNJ-31020028 is sufficient for estimating pharmacokinetic parameters. Thirdly, N-[11 C]methyl-JNJ-31020028 binds reversibly and competitively to cerebral sites. Fourthly, white matter such as pons can serve as reference region for simplified reference tissue model. To our knowledge, no other radioligand currently exists with these favorable properties and with this specificity for NPY2 receptors. Therefore, we view N-[11 C]methyl-JNJ-31020028 as
P.1.i. Basic and clinical neuroscience − Brain imaging and neuro-modulation
P.1.i. Basic and clinical neuroscience − Brain imaging and neuro-modulation P.1.i.001 Dopamine D2/3 receptor availability and human cognitive impulsivity: a high-resolution PET imaging study with [11 C]raclopride J.H. Kim1 ° , Y.D. Son2 , S.Y. Lee2 , Y.B. Kim3 , Z.H. Cho3 1 Gachon University Gil Medical Center, Department of Psychiatry, Incheon, South-Korea; 2 Gachon University, Neuroscience Research Institute, Incheon, South-Korea; 3 Gachon University, Neurosurgery Neuroscience Research Institute, Incheon, South-Korea Purpose of the study: Human impulsivity is a complex multidimensional construct encompassing cognitive, emotional, and behavioral aspects. Previous animal studies have suggested that striatal dopamine receptors play a critical role in impulsivity [1]. In this study, we investigated the relationship between self-reported impulsiveness and dopamine D2/ 3 receptor availability in striatal subdivisions in healthy subjects using high-resolution positron emission tomography (PET) with [11 C]raclopride. Methods: Twenty-one healthy normal subjects (8 men, 13 women; mean age: 34.6±8.8 years; mean years of education: 14.8±1.5) participated in the study after giving their written informed consent. All subjects completed PET scanning using the High-Resolution Research Tomograph (HRRT) system (Siemens Molecular Imaging, Knoxville, TN). Emission data were collected as listmode data in the 3-dimensional mode during the 60 minutes after [11 C]raclopride injection. The tracer [11 C]raclopride was synthesized by methylation of the desmethyl precursor using [11 C]iodomethane. To achieve accurate delineation of the brain regions for data analysis, each subject underwent a magnetic resonance imaging (MRI) scan using a 3-Tesla scanner (Magnetom Verio; Siemens, Germany). The MRI scan of each subject was coregistered to his or her PET scan using statistical parameter mapping software (SPM8). Regions of interest (ROIs) were drawn on each individual’s MRI. The striatum was divided into 5 anatomic ROIs, such as the ventral striatum (VST), the pre-commissural dorsal caudate (preDCA), the pre-commissural dorsal putamen (preDPU), the post-commissural caudate (postCA), and the post-commissural putamen (postPU), following the guidelines specified in the studies by Mawlawi et al. [2] and Martinez et al. [3]. Time-activity curves were generated for each ROI by averaging the dynamic PET images, which were coregistered to the corresponding MRI images. The distribution volume ratio (DVR) for [11 C]raclopride was obtained on the basis of the Logan graphical method. The trait of impulsiveness was measured using the Barratt Impulsiveness Scale (BIS-11). To control for the potentially confounding effects of general temperament characteristics that are conceptually or empirically related to dopamine, the Temperament and Character Inventory (TCI) was administered for measuring the biogenetic temperament of harm avoidance and novelty seeking. Partial correlation analysis was performed between BIS-11 scores and D2/ 3 receptor availability in striatal subregions, controlling for age and TCI scores. The level of statistical significance was defined as p < 0.05 (two-tailed). Results: The analysis revealed that the non-planning and attentional impulsiveness subscale scores of the BIS-11 had significant positive correlations with the DVR value of [11 C]raclopride in the
preDCA (non-planning: r = 0.65, p = 0.004, attentional: r = 0.61, p = 0.007). There was a tendency toward positive correlation between the non-planning impulsiveness score and the [11 C]raclopride DVR value in the postCA (r = 0.43, p = 0.075). No significant correlations were observed between the motor impulsiveness score and the [11 C]raclopride DVR values in any subregion. Conclusions: These results suggest that cognitive subtrait of impulsivity is associated with D2/ 3 receptor availability in the associative striatum that plays a critical role in cognitive processes involving attention to detail, judgment of alternative outcomes, and inhibitory control. References [1] Dalley, J.W., Fryer, T.D., Brichard, L., Robinson, E.S., Theobald, D.E., L¨aa¨ ne, K., Pe˜na, Y., Murphy, E.R., Shah, Y., Probst, K., Abakumova, I., Aigbirhio, F.I., Richards, H.K., Hong, Y., Baron, J.C., Everitt, B.J., Robbins, T.W., 2007. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315, 1267–1270. [2] Mawlawi, O., Martinez, D., Slifstein, M., Broft, A., Chatterjee, R., Hwang, D.R., Huang, Y., Simpson, N., Ngo, K., Van Heertum, R., Laruelle, M., 2001. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2)receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21, 1034–1057. [3] Martinez, D., Slifstein, M., Broft, A., Mawlawi, O., Hwang, D.R., Huang, Y., Cooper, T., Kegeles, L., Zarahn, E., Abi-Dargham, A., Haber, S.N., Laruelle, M., 2003. Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamineinduced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab 23, 285–300.
P.1.i.002 Subgenual anterior cingulate cortical functional connectivity in treatment-resistant depression C. Baeken1 ° , D. Marinazzo2 , G.R. Wu2 , P. Van Schuerbeek3 , J. De Mey3 , R. De Raedt4 1 Free University of Brussels, Dept of psychiatry, Brussels, Belgium; 2 Ghent University, Department of Data Analysis, Ghent, Belgium; 3 Free University of Brussels, Department of Radiology and Medical Imaging, Brussels, Belgium; 4 Free University of Brussels, Department of Experimental Clinical and Health Psychology, Ghent, Belgium Purpose of the study: Major depression disorder (MDD) is a worldwide mental health problem affecting millions. Unfortunately, not all patients respond to the available pharmacological treatment algorithms and refractory depression is not uncommon. Further, the phenomenon of treatment-resistant depression (TRD) still remains unclear. Because of the pervasive and persistent nature of depressive symptoms, resting-state fMRI has been proposed as a new promising neuroimaging technique to examine alterations of network connectivity in MDD patients at rest. In spite that the subgenual anterior cingulate cortex (sgACC) has consistently been documented to be deregulated in MDD no resting state functional connectivity (rsFC) studies yet focused on sgACC dysfunction in TRD. As it was stated that a stronger FC anti-correlation between the sgACC and distinct parts of the (dorsal) prefrontal cortex (DLPFC) could be indicative for clinical response to repetitive Transcranial Magnetic Stimulation (rTMS) [1], our research objective was to evaluate whether FC sgACC could differentiate high-frequency (HF)-rTMS (non) responders from never-depressed controls at baseline. Methods: We examined 20 antidepressant-free unipolar melancholic TRD patients (at least stage III) (Female:Male [F:M] =
P.1.i. Basic and clinical neuroscience − Brain imaging and neuro-modulation 15:4; mean age 49.4 y, sd 11.1) and 20 never-depressed individuals matched for age and gender (F:M = 15:4; mean age 44.9 y, sd 11.9). TRD patients were tapered-off their psychotropic drugs and all were medication-free for at least two weeks before scanning. Hereafter, only patients followed an intensive sham-controlled HF-rTMS treatment protocol applied to the left DLPFC [2]. Clinical response was defined as a 50% reduction of the baseline Hamilton Depression Rating Scale score. Fisher’s r-to-Z maps were submitted to a random-effect analysis in SPM8 in an independent Ti-test design containing age as covariate, thresholded with Alphasim correction with a cluster extent threshold (K) of 46 voxels and a voxel significance threshold of 0.05. The sgACC MNI coordinates were selected from Cisler [3] defining centroids of nodes comprising an affective cognitive network. Summary of results: Seven patients were identified as clinical responders after real HF-rTMS treatment and no patients responded to sham. Compared to the control group, TRD patients displayed significantly less sgACC FC with the right posterior cingulate gyrus (PCG) and significantly more sgACC FC with the right middle frontal gyrus. Importantly, our data also indicate that these FC sgACC differences seem to be driven by HF-rTMS responders and non-responders. Whereas HF-rTMS responders showed less sgACC FC with the right PCG, non-responders displayed stronger sgACC FC with the right prefrontal cortex. Conclusions: sgACC FC patterns are not univocal across depressed patients documented to be resistant to several pharmacotherapeutic interventions and can further be differentiated when such patients are responsive or not to non-invasive HF-rTMS treatment. Our results confirm the importance of PCG in MDD and the involvement of a continuous deregulation pattern between the sgACC and the right prefrontal cortex in HF-rTMS nonresponders. Our findings provide further insights into the complexity of sgACC deregulated networks and the possible indication for non-invasive neuromodulation options for TRD patients. References [1] Fox, M.D., Buckner, R.L., White, M.P., Greicius, M.D., PascualLeone, A., 2012 Efficacy of Transcranial Magnetic Stimulation Targets for Depression Is Related to Intrinsic Functional Connectivity with the Subgenual Cingulate. Biol Psychiatry 72, 595–603. [2] Zeeuws, D., De Rycker, K., De Raedt, R., De Beyne, M., Baeken, C., Vanderbruggen, N., 2011 Intensive high-frequency repetitive transcranial magnetic stimulation treatment in an electroconvulsive shock therapy-resistant bipolar I patient with mixed episode. Brain Stimul 4, 46−49. [3] Cisler, J.M., James, G.A., Tripathi, S., Mletzko, T., Heim, C., Hu, X.P., Mayberg, H.S., Nemeroff, C.B., Kilts, C.D., 2012 Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress. Psychol Med 10, 1−12.
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P.1.i.003 PET brain imaging of neuropeptide Y2 receptors D. Smith1 ° , M. Winterdahl2 , H. Audrain2 , A. Landau3 , P. Bonaventure4 , J. Shoblock4 , N. Carruthers4 , D. Swanson4 , D. Bender2 1 Aarhus University Hospital, Center for Psychiatric Research, Risskov, Denmark; 2 Aarhus University Hospital, PET Center, Aarhus, Denmark; 3 Aarhus University Hospital, PET Center & CFIN, Aarhus, Denmark; 4 Janssen Pharm, Research & Development, San Diego CA, USA Purpose of the study: Neuropeptide Y2 (NPY2) receptors are implicated in diverse brain disorders, but no suitable PET radiotracers are currently available for studying NPY2 receptors in the living brain. Therefore, we prepared a positron-emitting radioligand based on a novel NPY2 receptor antagonist, JNJ31020028, and used the compound for PET brain imaging in living pigs. In vitro receptor autoradiographic studies were also carried out to establish the anatomical distribution of NPY2 receptors in pig brain. Methods used: Yorkshire × Landrace pigs weighing 35−40 kg were used. Baseline and post-challenge PET recordings of N-[11 C]methyl-JNJ-31020028 in living pig brain were conducted for 90 min, concurrent with arterial blood sampling, and with unlabelled JNJ-31020028 as pharmacologic intervention. Cyclosporin A was used to enhance levels of the PET radiotracer in the brain. The PET images were manually coregistered to an MR atlas of the pig brain. Parametric images of the binding potentials of NPY2 receptors towards the N-[11 C]methyl-JNJ31020028 in the living brain were calculate using the simplified reference tissue method and compared to a three compartment plasma input model. Summary of results containing real data and appropriate statistical assessments: We noted high densities of N-[11 C]methyl-JNJ-31020028 receptor binding sites in autoradiography studies primarily in hippocampus; they were inhibited by unlabeled JNJ-31020028. In PET studies, N-[11 C]-methyl-JNJ31020028 was metabolized slowly in the bloodstream, with 25% of [11 C]-labeled parent compound remaining 30 minutes after injection. A strong linear correlation (r = 0.92; P = 0.01) was found between estimates of binding potentials obtained with a three compartment plasma input model and the simplified reference tissue method. The simplified reference tissue method showed baseline binding potentials of 0.55±0.02 in caudate nucleus, 0.49±0.03 in hippocampus, and 0.34±0.07 in frontal cortex. N-[11 C]methyl-JNJ31020028 binding was reversible, in that infusion of unlabeled JNJ-31020028 markedly displaced the PET radioligand from binding sites in caudate nucleus, hippocampus, and frontal cortex. Conclusions: N-[11 C]methyl-JNJ-31020028 is the first candidate radioligand with suitable properties for PET imaging of NPY2 receptors in the living brain. Firstly, it is metabolized slowly in the bloodstream, according to our studies in pigs. Secondly, using cyclosporin, the target-to-background ratio of N-[11 C]methylJNJ-31020028 is sufficient for estimating pharmacokinetic parameters. Thirdly, N-[11 C]methyl-JNJ-31020028 binds reversibly and competitively to cerebral sites. Fourthly, white matter such as pons can serve as reference region for simplified reference tissue model. To our knowledge, no other radioligand currently exists with these favorable properties and with this specificity for NPY2 receptors. Therefore, we view N-[11 C]methyl-JNJ-31020028 as