Molecular imaging of striatal and extrastriatal components of the dopamine system: positron emission tomographic studies in healthy subjects and Parkinson Disease

Dopamine plays a pivotal role in the regulation and control of cognition, movement and motivation and is involved in a variety of neurological and psychiatric disorders. Molecular imaging with positron emission tomography (PET) and radiolabeled compounds has enabled the in vivo assessment of the distribution and density of receptors, enzymes and other cellular processes pertaining to the dopamine system in normal and pathological states. Until recently, such measurements have been restricted to the striatum, due to the paucity of appropriate radioligands for measurement of low density targets. With the development of radioligands suitable for extrastriatal measurement, examination of the different components of the dopamine system in not only the striatum, but also extrastriatal regions, is possible, in living human brain. Therefore, the aims of this thesis were to assess, by means of two independent experimental PET studies, the feasibility of imaging pre-, post- and intra-synaptic components of the dopamine system in the striatum, as well as extrastriatal areas. Change in dopamine markers were assessed in human subjects with a compromised dopamine system, altered by pharmacological (Study 1) or pathological (Study 2) means. Specifically, intra-synaptic dopamine transmission (“phasic” and “tonic” dopamine release) was examined with [18F]fallypride (for post-synaptic D2-like receptors) and pharmacological challenges to either increase or decrease dopamine transmission in young healthy subjects (Study 1), whereas pre- and post-synaptic dopamine transmission was assessed with [18F]FDOPA (for pre-synaptic dopamine synthesis) and [11C]NNC 112 (for post-synaptic D1-like receptors) in a patient cohort characterised by chronic dopamine deficiency (Parkinson disease) (Study 2). In each study, associations between these dopamine markers and higher cognitive functions were explored. Findings confirm that [18F]fallypride and [11C]NNC 112 are able to be quantified in striatal and extrastriatal regions. Cortical [18F]FDOPA uptake however, was unable to be quantified. Stimulant-induced dopamine release with d-amphetamine successfully displaced [18F]fallypride binding in striatum and several extrastriatal regions. However, depletion of dopamine with AMPT did not appear to modulate [18F]fallypride in any region (Study 1). Parkinson disease patients did not show alteration of striatal or cortical D1 receptors despite significantly reduced dopamine metabolism in the striatum, which was associated with executive impairment (Study 2). These studies demonstrate the capability of PET, with radioligands targeting presynaptic synthesis and post-synaptic D1 and D2 receptors, to assess different components of the dopamine system in striatum and extrastriatum. The pitfalls and complexity of radioligand imaging are discussed within the context of [18F]fallypride, [11C]NNC 112 and [18F]FDOPA measurement. Lastly, this thesis demonstrates some promise for using molecular imaging to explore the neurochemical underpinnings of higher cortical function.