Basal dopamine occupancy estimation with simultaneous PET/fMRI
Christin Y. Sander, Massachusetts General Hospital; Harvard Medical School
Objectives: Basal receptor occupancy by endogenous neurotransmitter cannot be measured with PET without depleting the entire neurotransmitter population, which has major side effects1. We have previously shown that occupancy and fMRI signal are linearly related for a D2/D3 antagonist2, from which relative basal dopamine (DA) levels can be inferred. For this study, we propose to derive absolute basal DA levels occupancies in vivo using an antagonist-agonist pair and simultaneous PET/fMRI.
Methods: Simultaneous PET/fMRI was acquired in two anesthetized non-human primates with the radiotracer [11C]raclopride and graded D2/D3 pharmacological challenges: antagonist raclopride (0.4, 1.4, 4.5, 16, 41 μg/kg) and agonist quinpirole (0.1, 0.2, 0.3 mg/kg). fMRI data were analyzed with the GLM and signals converted to cerebral blood volume (CBV)3. PET kinetic modeling was performed with SRTM24 using a time-dependent binding parameter5, from which occupancies were derived. A generalized neurovascular coupling model was established to compute absolute basal DA occupancy levels.
Results & Discussion: Dose-dependent signal changes were observed for both agonist and antagonist, albeit with different response patterns. Fig. 1 shows a plot of CBV vs. occupancy (θ), demonstrating a monotonically increasing/decreasing function but with distinct slopes for antagonist/agonist. The voxelwise maps on the right show that the relative CBV magnitude in putamen and caudate is reversed for agonist and antagonist. Interestingly, CBV magnitudes of antagonist were larger compared to agonist at matching occupancies, and shorter fMRI timecourses were observed for the latter. These experimental observations are consistent with agonist-induced internalization and suggest that neurovascular coupling constants (N) cannot be assumed to be constant between antagonist/agonist. Our proposed coupling model shows that CBV signal is ∝NAntεAnt(θ(0)DAθAnt) in the antagonist case, but ∝NAg((εAg – θ(0)DA)θAg) in the agonist case, with θ(0)DA the basal occupancy and ε the efficacy of the drug. Since a direct application of the model to estimate absolute basal DA occupancies from one drug and anatomical region is not possible without assuming NAnt=NAnt, we employed ratios of the neurovascular coupling expressions between regions and injected drugs. θ(0)DA was thus determined as ~10% in caudate and ~20% in putamen, which is consistent with reported literature values6.
Conclusion: Our approach using ratios of an agonist/antagonist pair and anatomical regions enables the estimation of absolute basal neurotransmitter occupancies. This method is not affected by distinct function-occupancy relationships of agonists/antagonists. Further studies with varying efficacies of ligands can further validate this technique. The ability to measure basal DA occupancies non-invasively and without major side effects is important for its application as a clinical biomarker in psychiatric and neurologic disease.
References:
1Abi-Dargham et al. PNAS (2000).
2Sander et al. PNAS (2013).
3Mandeville et al. MRM (1998).
4Ichise et al. JCBFM (2003).
5Normandin et al. NeuroImage (2012).
6Pifl et al. Neurochem. Int. (2006).
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