Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses

Philipp T. Meyer, Zubin Bhagwagar, Philip J. Cowen, Vincent J. Cunningham, Paul M. Grasby, Rainer Hinz

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: [C-11]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT2A receptor quantification in vivo. Studies suggest that [C-11]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. Methods: Five healthy volunteers underwent [C-11]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time-activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BPND) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BPND maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BPND, which were highly correlated with 2TCM analyses (R-2 >= 0.86) although with negative bias (-29 +/- 27% at baseline across all ROI). NIGA was less biased (-19 +/- 16%) and better correlated with 2TCM (R-2 >= 0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed Comparable mean biases (-11 +/- 27% vs. -7 +/- 47%) but correlation with 2TCM was higher for NIGA (R-2 = 0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BPND (-26 +/- 22%; R-2 >= 0.88) and Occ (-17 +/- 36%: R-2 = 0.78). Estimates obtained from tissue ratios performed least favourably. Conclusions: NIGA is well suited for analysis of [C-11]MDL100,907 PET studies, yielding estimates of 5-HT2A receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT2A receptor PET studies.

Original languageEnglish
Pages (from-to)984-993
Number of pages10
JournalNeuroimage
Volume50
Issue number3
Early online date18 Jan 2010
DOIs
Publication statusPublished - 15 Apr 2010

Keywords

  • [C-11]MDL 100,907
  • 5-HT2A receptor
  • positron emission tomography
  • tracer kinetic modelling
  • reference region
  • positron-emission-tomography
  • graphical analysis method
  • reference tissue model
  • living human-brain
  • serotonin receptors
  • binding
  • dopamine
  • ligand
  • neuroreceptor
  • radioligand

Cite this

Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses. / Meyer, Philipp T.; Bhagwagar, Zubin; Cowen, Philip J.; Cunningham, Vincent J.; Grasby, Paul M.; Hinz, Rainer.

In: Neuroimage, Vol. 50, No. 3, 15.04.2010, p. 984-993.

Research output: Contribution to journalArticle

Meyer, Philipp T. ; Bhagwagar, Zubin ; Cowen, Philip J. ; Cunningham, Vincent J. ; Grasby, Paul M. ; Hinz, Rainer. / Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses. In: Neuroimage. 2010 ; Vol. 50, No. 3. pp. 984-993.
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abstract = "Background: [C-11]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT2A receptor quantification in vivo. Studies suggest that [C-11]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. Methods: Five healthy volunteers underwent [C-11]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time-activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BPND) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BPND maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BPND, which were highly correlated with 2TCM analyses (R-2 >= 0.86) although with negative bias (-29 +/- 27{\%} at baseline across all ROI). NIGA was less biased (-19 +/- 16{\%}) and better correlated with 2TCM (R-2 >= 0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed Comparable mean biases (-11 +/- 27{\%} vs. -7 +/- 47{\%}) but correlation with 2TCM was higher for NIGA (R-2 = 0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BPND (-26 +/- 22{\%}; R-2 >= 0.88) and Occ (-17 +/- 36{\%}: R-2 = 0.78). Estimates obtained from tissue ratios performed least favourably. Conclusions: NIGA is well suited for analysis of [C-11]MDL100,907 PET studies, yielding estimates of 5-HT2A receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT2A receptor PET studies.",
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T1 - Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses

AU - Meyer, Philipp T.

AU - Bhagwagar, Zubin

AU - Cowen, Philip J.

AU - Cunningham, Vincent J.

AU - Grasby, Paul M.

AU - Hinz, Rainer

PY - 2010/4/15

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N2 - Background: [C-11]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT2A receptor quantification in vivo. Studies suggest that [C-11]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. Methods: Five healthy volunteers underwent [C-11]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time-activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BPND) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BPND maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BPND, which were highly correlated with 2TCM analyses (R-2 >= 0.86) although with negative bias (-29 +/- 27% at baseline across all ROI). NIGA was less biased (-19 +/- 16%) and better correlated with 2TCM (R-2 >= 0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed Comparable mean biases (-11 +/- 27% vs. -7 +/- 47%) but correlation with 2TCM was higher for NIGA (R-2 = 0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BPND (-26 +/- 22%; R-2 >= 0.88) and Occ (-17 +/- 36%: R-2 = 0.78). Estimates obtained from tissue ratios performed least favourably. Conclusions: NIGA is well suited for analysis of [C-11]MDL100,907 PET studies, yielding estimates of 5-HT2A receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT2A receptor PET studies.

AB - Background: [C-11]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT2A receptor quantification in vivo. Studies suggest that [C-11]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. Methods: Five healthy volunteers underwent [C-11]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time-activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BPND) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BPND maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BPND, which were highly correlated with 2TCM analyses (R-2 >= 0.86) although with negative bias (-29 +/- 27% at baseline across all ROI). NIGA was less biased (-19 +/- 16%) and better correlated with 2TCM (R-2 >= 0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed Comparable mean biases (-11 +/- 27% vs. -7 +/- 47%) but correlation with 2TCM was higher for NIGA (R-2 = 0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BPND (-26 +/- 22%; R-2 >= 0.88) and Occ (-17 +/- 36%: R-2 = 0.78). Estimates obtained from tissue ratios performed least favourably. Conclusions: NIGA is well suited for analysis of [C-11]MDL100,907 PET studies, yielding estimates of 5-HT2A receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT2A receptor PET studies.

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KW - 5-HT2A receptor

KW - positron emission tomography

KW - tracer kinetic modelling

KW - reference region

KW - positron-emission-tomography

KW - graphical analysis method

KW - reference tissue model

KW - living human-brain

KW - serotonin receptors

KW - binding

KW - dopamine

KW - ligand

KW - neuroreceptor

KW - radioligand

U2 - 10.1016/j.neuroimage.2010.01.037

DO - 10.1016/j.neuroimage.2010.01.037

M3 - Article

VL - 50

SP - 984

EP - 993

JO - Neuroimage

JF - Neuroimage

SN - 1053-8119

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ER -