Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress

Logan, Jean; Wang, Gene‐Jack; Telang, Frank; Fowler, Joanna S.; Alexoff, David; Zabroski, John; Jayne, Millard; Hubbard, Barbara; King, Payton; Carter, Pauline; Shea, Colleen; Xu, Youwen; Muench, Lisa; Schlyer, David; Learned-Coughlin, Susan; Cosson, Valérie; Volkow, Nora D.; Ding, Yu‐Shin

doi:10.1016/j.nucmedbio.2007.03.013

Cited by 67 publications

(67 citation statements)

References 39 publications

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“…The locus coeruleus showed relatively high uptake, and the hippocampus and anterior cingulate cortex showed relatively low uptake. This result was in agreement with previous reports that the thalamus and locus coeruleus showed high densities of norepinephrine transporters (14)(15)(16)20). Previous autoradiographic studies with human postmortem brains reported that norepinephrine transporter density in the locus coeruleus was higher by about 10 times than that in the thalamus (14,15).…”

Section: Discussionsupporting

confidence: 93%

“…Previous autoradiographic studies with human postmortem brains reported that norepinephrine transporter density in the locus coeruleus was higher by about 10 times than that in the thalamus (14,15). However, previous and present PET studies reported almost the same values between the locus coeruleus and thalamus (10,16). One possible reason for the discrepancy was the partialvolume effect due to the limited spatial resolution of the PET scanner, the locus coeruleus being a very small structure.…”

Section: Discussioncontrasting

confidence: 82%

“…The results could be explained if the caudate contained specific binding for norepinephrine transporters. However, previous autoradiographic studies showed that the density of norepinephrine transporters in the caudate was very low (14)(15)(16). Another possible explanation is that the compartments of free and nonspecific binding could be separated by the kinetic analysis.…”

Section: Discussionmentioning

confidence: 95%

“…Previous animal studies showed dose-dependent norepinephrine transporter occupancy by atomoxetine (12). However, a human study using [ 11 C](S,S)-MRB reported no differences in occupancy between different doses of atomoxetine (16). Further, occupancy studies in humans to estimate the clinical effects of antidepressants, similar to occupancy studies for dopamine D 2 receptor and serotonin transporters (23,24), will be needed.…”

Section: Discussionmentioning

confidence: 99%

“…In these methods, (S,S)-18 F-FMeNER-D 2 bindings were expressed as binding potentials relative to nondisplaceable binding (BP ND ) (13). We used the caudate as the reference brain region because of its negligible norepinephrine transporter density (14)(15)(16). Software (PMOD; PMOD Technologies) was used for these analyses.…”

Section: Kinetic Model Of 18 F-fmener-dmentioning

confidence: 99%

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Quantitative Analysis of Norepinephrine Transporter in the Human Brain Using PET with (S,S)-¹⁸F-FMeNER-D₂

Arakawa¹,

Okumura²,

Ito³

et al. 2008

J Nucl Med

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(S,S)-18 F-FMeNER-D 2 was recently developed as a radioligand for the measurement of norepinephrine transporter imaging with PET. In this study, a norepinephrine transporter was visualized in the human brain using this radioligand with PET and quantified by several methods. Methods: PET scans were performed on 10 healthy men after intravenous injection of (S,S)-18 FFMeNER-D 2 . Binding potential relative to nondisplaceable binding (BP ND ) was quantified by the indirect kinetic, simplified reference-tissue model (SRTM), multilinear reference-tissue model (MRTM), and ratio methods. The indirect kinetic method was used as the gold standard and was compared with the SRTM method with scan times of 240 and 180 min, the MRTM method with a scan time of 240 min, and the ratio method with a time integration interval of 120-180 min. The caudate was used as reference brain region. Results: Regional radioactivity was highest in the thalamus and lowest in the caudate during PET scanning. BP ND values by the indirect kinetic method were 0.54 6 0.19 and 0.35 6 0.25 in the thalamus and locus coeruleus, respectively. BP ND values found by the SRTM, MRTM, and ratio methods agreed with the values demonstrated by the indirect kinetic method (r 5 0.81-0.92). Conclusion: The regional distribution of (S,S)-18 F-FMeNER-D 2 in our study agreed with that demonstrated by previous PET and postmortem studies of norepinephrine transporter in the human brain. The ratio method with a time integration interval of 120-180 min will be useful for clinical research of psychiatric disorders for estimation of norepinephrine transporter occupancy by antidepressants without requiring arterial blood sampling and dynamic PET.

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Section: Discussionsupporting

confidence: 93%

Section: Discussioncontrasting

confidence: 82%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Kinetic Model Of 18 F-fmener-dmentioning

confidence: 99%

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Quantitative Analysis of Norepinephrine Transporter in the Human Brain Using PET with (S,S)-¹⁸F-FMeNER-D₂

Arakawa¹,

Okumura²,

Ito³

et al. 2008

J Nucl Med

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Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Transporter Availability in the Locus Coeruleus

et al. 2013

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The Norepinephrine Transporter in Attention-Deficit/Hyperactivity Disorder Investigated With Positron Emission Tomography

et al. 2014

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IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) research has long focused on the dopaminergic system's contribution to pathogenesis, although the results have been inconclusive. However, a case has been made for the involvement of the noradrenergic system, which modulates cognitive processes, such as arousal, working memory, and response inhibition, all of which are typically affected in ADHD. Furthermore, the norepinephrine transporter (NET) is an important target for frequently prescribed medication in ADHD. Therefore, the NET is suggested to play a critical role in ADHD.OBJECTIVE To explore the differences in NET nondisplaceable binding potential (NET BP ND ) using positron emission tomography and the highly selective radioligand (S,S)-between adults with ADHD and healthy volunteers serving as controls. DESIGN, SETTING, AND PARTICIPANTS Twenty-two medication-free patients with ADHD (mean [SD] age, 30.7 [10.4] years; 15 [68%] men) without psychiatric comorbidities and 22 age-and sex-matched healthy controls (30.9 [10.6] years; 15 [68%] men) underwent positron emission tomography once. A linear mixed model was used to compare NET BP ND between groups. MAIN OUTCOMES AND MEASURESThe NET BP ND in selected regions of interest relevant for ADHD, including the hippocampus, putamen, pallidum, thalamus, midbrain with pons (comprising a region of interest that includes the locus coeruleus), and cerebellum. In addition, the NET BP ND was evaluated in thalamic subnuclei (13 atlas-based regions of interest). RESULTSWe found no significant differences in NET availability or regional distribution between patients with ADHD and healthy controls in all investigated brain regions (F 1,41 < 0.01; P = .96). Furthermore, we identified no significant association between ADHD symptom severity and regional NET availability. Neither sex nor smoking status influenced NET availability. We determined a significant negative correlation between age and NET availability in the thalamus (R 2 = 0.29; P < .01 corrected) and midbrain with pons, including the locus coeruleus (R 2 = 0.18; P < .01 corrected), which corroborates prior findings of a decrease in NET availability with aging in the human brain.CONCLUSIONS AND RELEVANCE Our results do not indicate involvement of changes in brain NET availability or distribution in the pathogenesis of ADHD. However, the noradrenergic transmitter system may be affected on a different level, such as in cortical regions, which cannot be reliably quantified with this positron emission tomography ligand. Alternatively, different key proteins of noradrenergic neurotransmission might be affected.

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Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress

Cited by 67 publications

References 39 publications

Quantitative Analysis of Norepinephrine Transporter in the Human Brain Using PET with (S,S)-¹⁸F-FMeNER-D₂

Quantitative Analysis of Norepinephrine Transporter in the Human Brain Using PET with (S,S)-¹⁸F-FMeNER-D₂

Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Transporter Availability in the Locus Coeruleus

The Norepinephrine Transporter in Attention-Deficit/Hyperactivity Disorder Investigated With Positron Emission Tomography

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Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress

Cited by 67 publications

References 39 publications

Quantitative Analysis of Norepinephrine Transporter in the Human Brain Using PET with (S,S)-18F-FMeNER-D2

Quantitative Analysis of Norepinephrine Transporter in the Human Brain Using PET with (S,S)-18F-FMeNER-D2

Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Transporter Availability in the Locus Coeruleus

The Norepinephrine Transporter in Attention-Deficit/Hyperactivity Disorder Investigated With Positron Emission Tomography

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Quantitative Analysis of Norepinephrine Transporter in the Human Brain Using PET with (S,S)-¹⁸F-FMeNER-D₂

Quantitative Analysis of Norepinephrine Transporter in the Human Brain Using PET with (S,S)-¹⁸F-FMeNER-D₂