Characterisation of [11C]PR04.MZ in Papio Anubis Baboon: A Selective High-Affinity Radioligand for Quantitative Imaging of the Dopamine Transporter

N-(4-fluorobut-2-yn-1-yl)-2b-carbomethoxy-3b-(40-tolyl)nortropane (PR04.MZ, 1) is a PET radioligand for the non-invasive exploration of the function of the cerebral dopamine transporter (DAT). A reliable automated process for routine production of the carbon-11 labelled analogue [C]PR04.MZ ([C]-1) has been developed using GMP compliant equipment. An adult female Papio anubis baboon was studied using a test–retest protocol with [C]-1 in order to assess test–retest reliability, metabolism and CNS distribution profile of the tracer in non-human primates. Blood sampling was performed throughout the studies for determination of the free fraction in plasma (fP), plasma input functions and metabolic degradation of the radiotracer [C]-1. Time–activity curves were derived for the putamen, the caudate nucleus, the ventral striatum, the midbrain and the cerebellum. Distribution volumes (VT) and non-displaceable binding potentials (BPND) for various brain regions and the blood were obtained from kinetic modelling. [C]-1 shows promising results as a selective marker of the presynaptic dopamine transporter. With the reliable visualisation of the extra-striatal dopaminergic neurons and no indication on labelled metabolites, the tracer provides excellent potential for translation into man. 2011 Elsevier Ltd. All rights reserved. Presynaptic membrane transporter mediated neurotransmitter dopaminergic degradation in the substantia nigra causes the downreuptake is crucial for themediation ofmonoamine signal transduction. Imagingof theneurotransmitter sodiumsymporterswithpositron emission tomography (PET) provides valuable insights into reuptake dysfunction and function of the neuron. PET studies of the dopamine transporter (DAT) provide information on the presynaptic integrity of the dopaminergic system in psychiatric andmovement disorders. Radiolabelled DAT-ligands are established for the early clinical diagnosis of Parkinson’s disease (PD) and the differentiation of PD from symptomatically related disorders. A variety of compounds has already been evaluated and utilised for studies of the striatal DAT. Cocaine derived phenyltropanes have emerged from these studies as the most appropriate imaging agents for this purpose. However, particular limitations of these agents include low selectivity of the ligand over the serotonin transporter (SERT) and the norepinephrine transporter (NET), blood brain barrier penetrating metabolites, non-specific binding and slow binding equilibrium. Moreover, there is an unmet need for a high affinity radioligand suitable for the visualisation of lowdensityDAT populations outside the striatum particularly given the fact that the dopaminergic signal pathways originate in the midbrain and ll rights reserved. stream effects of PD in the striatum. This brain region also shows pathologic alterations in children with attention deficit/hyperactivity syndrome (ADHS). Nevertheless, only a fewDAT studies targeting the midbrain region, have been performed due to the absence of appropriate imaging agents. We were interested in the cerebral distribution, metabolism and initial kinetic modelling results of N-(4-fluorobut-2-yn-1-yl)2b-carbomethoxy-3b-(40-tolyl)nortropane (PR04.MZ, 1), a promising radiotracer from our laboratories, in non-human primates. PR04.MZ is a high affinity (IC50hDAT: 2 nM) DAT-selective (SERT/ DAT-selectivity: >50; NET/DAT-selectivity: >10) competitive inhibitor of monoamine reuptake but not a substrate for the DAT. Its affinity exceeds the figures reported for other established DAT-ligands, such as PE2I (Kd(rat): 4 nM), FECNT (Ki: 8 nM) or LBT-999 (Kd(rat): 9 nM). Moreover, indications of superior selectivity have been reported recently. In vitro monoamine transporter inhibition potency and selectivity as well as an experimental logD value of 1 are summarised in Table 1. The molecular structure of 1 provides two sites for the straightforward incorporation of either carbon-11 or fluorine-18. Radiolabelling with both PET nuclides has been communicated recently. Moreover, an automated process for the production of the carbon-11 labelled radiotracer [C]-1 has been developed to facilitate upcoming human studies.