title: Age-related changes in binding of the D2/3 receptor radioligand [(11)C](+)PHNO in healthy volunteers.
abstract: OBJECTIVE
  Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [(11)C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age.
  
  
  METHODS
  Forty-two healthy control subjects (9 females, 33 males; age range 19-55 years) were scanned with [(11)C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images.
  
  
  RESULTS
  Regional [(11)C](+)PHNO BPND displayed a negative correlation between receptor availability and age in the caudate (r=-0.56, corrected p=0.0008) and putamen (r=-0.45, corrected p=0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions.
  
  
  CONCLUSIONS
  In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [(11)C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA; Department of Psychiatry, Yale University, New Haven, CT, USA. Electronic address: david.matuskey@yale.edu.
authors.forename: David
authors.initials: D
authors.lastname: Matuskey
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Worhunksy
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Correa
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Pittman
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Sreeram
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Gudepu
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA; Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Gaiser
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA; Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Cosgrove
authors.affiliation: Department of Radiology, New York University School of Medicine, New York, NY, USA; Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA; Department of Neurobiology, Yale University, New Haven, CT, USA; Department ofChild Study Center, Yale University, New Haven, CT, USA.
authors.forename: Marc N
authors.initials: MN
authors.lastname: Potenza
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Malison
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists / Q000493:pharmacokinetics*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; C581293:DRD2 protein, human; D018492:Dopamine Antagonists; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3
keywords: Aging; D(2)R; D(3)R; Dopamine; PET imaging; [(11)C](+)PHNO