In vivo quantification of extrastriatal dopamine D2 receptors in the human brain

Abstract

The dopamine D2 receptor subtype attracts considerable attention in research on the patophysiology and drug treatment of several neuropsychiatric disorders, such as schizophrenia and Parkinson's disease. The brain imaging technology Positron Emission Tomography (PET) has since long allowed for reliable quantification of the high density of dopamine D2 receptors in large brain structures such as the neostriatum. Several extrastriatal brain regions with low dopamine D2 receptor density are of central interest in current hypotheses on the role of dopaminergic neurotransmission in neuropsychiatric disorders. New methodologies are required for this purpose.

The radioligand [11C]FLB 457 has the very high affinity of 20 pM for dopamine D2 receptors in vitro and allows for visualization of binding to the minute concentrations of dopamine D2 receptors in extrastriatal regions in the human brain in vivo. The overall aim of the present thesis was to examine and compare methodologies for quantification of regional [11C]FLB 457 binding in the living human brain.

Altogether ten control subjects participated in twenty-six PET measurements. To obtain absolute values for dopamine D2 receptor density and affinity, each subject participated in two to three PET measurements with different mass of radioligand injected. A metabolite corrected arterial input function was used in standard compartment model analyses and the cerebellum was evaluated as reference region in simplified quantitative approaches including a Scatchard analysis. Due to the lack of a simple analytical solution for the non-linear two-tissue compartment model, simulations were performed to understand the temporal behavior of radioligand binding.

[11C]FLB 457 binding to extrastriatal regions could be described by the two-tissue compartment model and the rank order of regional binding potential (BP) values was consistent with the rank order reported in binding studies on human brain tissue postmortem. Experimental data and simulation studies showed that the time to reach peak of specific radioligand binding is dependent on regional receptor density and varied between 39 and 63 minutes due to the several-fold difference in dopamine D2 receptor density across brain regions. Ratio methods underestimate drug-induced occupancy particularly in regions with high receptor density whereas the Simplified Reference Tissue Model (SRTM) yielded valid estimations. However, the BP obtained for the striatum, i.e. the region with highest density, was underestimated since 11Clabeled FLB 457 only allows for an acquisition time of about 1 hour.

The regional receptor density (Bmax) values obtained by Scatchard analysis were close to the in vitro values given in the literature. The affinity was about 10 to 20 times lower in vivo indicating that the free radioligand concentration in the extracellular space represents only a minor fraction of non-displaceable radioligand in brain. With regard to the cerebellum as reference region for non-displaceable binding it can not be excluded that [11C]FLB 457 is sensitive to the minute receptor density of dopamine D2 receptors in this region. Theoretical considerations illustrated by a simulation approach showed that the emerging concept of receptor occupancy half-life is not supported by theory. Instead, initial receptor occupancy and the time-constant for drug clearance in plasma can be used in clinical studies to estimate the net-dissociation of a drug from the receptors. Finally, it was shown that [11C]FLB 457 can be used to visualize and quantify binding in the non-diseased human pituitary. The calculated receptor density is consistent with in vitro values.

The thesis work shows that the PET radioligand [11C]FLB 457 can be used in vivo in the human brain to obtain valid estimates of binding parameters in extrastriatal brain regions containing dopamine D2 receptors as well as in the pituitary gland. Due to the short half-life of carbon-11, [11C]FLB 457 cannot be used in regions with high receptor density, such as the striatum. The methodology can be applied in clinical studies on hypotheses regarding the role of the extrastriatal dopamine systems in neuropsychiatric disorders.