Age-related changes in binding of the D2/3 receptor radioligand [(11)C](+)PHNO in healthy volunteers

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.

Conclusion: 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.