Objective: To investigate with PET and the radioligand [¹¹C]PHNO whether levodopa-induced dyskinesias in Parkinson disease (PD) are associated with dopamine-D3 receptor (D3R) overexpression in substantia nigra (SN).

Background: Increased [¹¹C]PHNO binding has been reported in striatal regions of PD patients with dyskinesia but not in the SN. However, while [¹¹C]PHNO has enabled quantification of the D3R in the human brain in vivo, its selectivity for the D3R is still not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). Therefore, with  the standard [¹¹C]PHNO PET paradigm used in previous studies, it remains unclear whether dyskinesias are associated with D2R or D3R overexpression.

Method: We used a novel [¹¹C]PHNO PET paradigm to provide a better estimation of the regional fractions of the [¹¹C]PHNO signal attributable to D3R binding in PD patients with dyskinesias (n = 6) and without dyskinesias (n = 7). We scanned the patients twice, injecting 300 MBq of [¹¹C]PHNO in co-administration with two doses (low and high) of unlabeled PHNO. To disregard D2R from D3R in the [¹¹C]PHNO signal, the regional fractions of the signal was measured as difference between low and high divided by high [¹¹C]PHNO ([¹¹C]PHNO ratio). This ratio provides an estimation of [¹¹C]PHNO signal attributable to D3R binding. Severity of dyskinesias was measured using the Abnormal Involuntary Movement Scale (AIMS).

Results: We found that PD patients with dyskinesia had higher [¹¹C]PHNO ratio in the SN compared to PD patients without dyskinesia (p=0.010), suggesting upregulation of D3R. Higher [¹¹C]PHNO in SN was associated with higher AIMS scores (rho=0.793; p=001), suggesting that the degree of D3R upregulation correlated with the severity of dyskinesias.

Conclusion: D3R upregulation in the SN might play a role in the development of dyskinesia. The findings support therapeutic strategies that target and diminish activity at D3 to prevent the development of dyskinesia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/levodopa-induced-dyskinesias-and-substantia-nigra-dopamine-d3-receptor-availability-in-parkinsons-disease/