Design and evaluation of novel PET and SPECT tracers for imaging the monoamine system and the P-gp transporter

Abstract

SPECT and PET are non-invasive imaging techniques in which radiotracers are used to study biochemical and physiological functions in the living brain. In vivo brain mapping with PET or SPECT can be of great importance in drug development as well as in the effective diagnosis, treatment and management of neurological and psychiatric disorders and substance abuse. Therefore, the development of new and more specific and selective radiotracers is of great importance in neuroimaging. In this thesis, new SPECT or PET radioligands directed towards two different brain elements, being the monoamine system and the P-gp transporter, were developed and evaluated in vivo. The first objective of this thesis was the design of radiotracers for the monoamine system more specifically, the norepinephrine transporter, monoamine oxidase and dopamine transporter which are all responsible for neurotransmitter inactivation. The synthesis, radiosynthesis and preliminary evaluation of [123I]-(S,S)-IPBM, an iodinated reboxetine analogue aimed to visualize the norepinephrine transporter is reported. In a following section, the radiolabelling as well as the in vivo characterization of two [11C]-labelled pyrrole-2-carboxamide derivatives are described. In vitro, they were both potent inhibitors of monoamine oxidase-A. The synthesis along with the radiolabelling and in vivo evaluation of [123I]-FMIP as a selective radiotracer for the dopamine transporter is reported. FMIP has nanomolar affinity for the dopamine transporter and better selectivity over the other monoamine transporters compared to the already existing ligands for dopamine transporter imaging with SPECT. In the last part of this thesis, the focus was redirected towards imaging of the P-glycoprotein transporter. The contribution of P-gp to the low brain uptake of [123I]-FMIP along with its potential as P-gp imaging agent are investigated. Finally, the radiolabelling of an in vitro characterized substrate (MC80) of the P-gp pump with 11C and the evaluation of this tracer in vivo for its potential to image P-gp function or expression is described