PET imaging of DA neurotransmission using agonist versus antagonist radiotracers

An increasingly important and intriguing application of positron emission tomography (PET) is to measure endogenous levels of neurotransmitters in vivo in both man and animals. Direct measurement of neurotransmitter levels is not achieved; rather the technique hinges on the competition between the levels of endogenous neurotransmitter and the PET radiotracer. In this context, changes in endogenous levels of dopamine (DA) have been extensively studied using the antagonist PET radioligand [11C]-raclopride. However, even though, the “raclopride-displacement” technique is widely used and has already provided important empirical findings in diseases and normal neurophysiology, it suffers from major methodological limitations. Some of these limitations have led to a re-assessment of the simple competition model used in this PET paradigm. We recently obtained in vitro and in vivo preclinical data supporting a mixed competitive and non-competitive action of DA on [11C]-raclopride binding, a finding that can reconcile the short-lasting changes in DA levels and the long-lasting changes in “raclopride-displacement” observed after amphetamine. However, limitations to the model still exist and, in particular, it is noteworthy that a substantial portion of antagonist radiotracer binding is impervious to DA manipulations. The so-called “ceiling effect” to the “raclopride-displacement” can be related directly to the inability of the antagonist radiotracers to distinguish low- from high-affinity states D2-receptors. Currently, there is tremendous emphasis on developing agonist D2-radioligands to circumvent this limitation. By competing directly for the same high affinity sites as DA, a full agonist radiotracer at the D2-receptor should exhibit increased sensitivity to DA levels when compared to antagonists, and also should show full displacement at very high levels of endogenous DA. We are at a moment of opportunity for testing these hypotheses as we recently developed the D2-agonist radiotracer [11C]-(+)-PHNO for this purpose. Pre-clinical evaluation demonstrated that [11C]-(+)-PHNO is selective for D2-receptors and showed an increased sensitivity to endogenous DA when compared to [11C]-raclopride, making it a very promising radioligand for imaging the high affinity state D2-receptor using PET. Preliminary work in humans demonstrated that [11C]-(+)-PHNO has favourable in vivo kinetics and displays a high signal to noise ratio in brain. The aim of this talk is to describe some of our experiences in the field. The focus will be primarily on imaging DA neurotransmission using PET, comparing and contrasting [11C]-raclopride and [11C]-(+)-PHNO. The ability to selectively probe the functionally active state of D2-receptors with [11C]-(+)-PHNO should increase our understanding of critical pathophysiological changes that occur in a number of DA-related illnesses such as schizophrenia, Huntington's disease and Parkinson's disease.