Patel, N; (2015) Development of Radiotracers for Neuroimaging (Patel, N, Trans.). Doctoral thesis , UCL (University College London).

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Abstract

Nuclear imaging enables quantitative measurements of biological processes in vivo and has revolutionised biomedical research, drug development and clinical practice. Despite the advances made in this field, the ability to image fundamental aspects of neurological diseases remains a challenge. This is partly due to the limited availability of radiotracers for imaging excitatory neurotransmission and detection of inflammation as well as an array of other biochemical processes central to the operational function of the brain. The aim of this research was to expand the arsenal of radiotracers available for neuroimaging in order to study key pathological processes involved in neurological diseases. With the aim to target neuronal Voltage Gated Sodium Channels (VGSCs), Vascular Cell Adhesion Molecule – 1 (VCAM-1) and N-methyl-D-Aspartate Receptors (NMDARs), radiotracers have been synthesised and evaluated. Abnormal expression of these receptors has been implicated in a number of pathological conditions including epilepsy, multiple sclerosis and neurodegeneration. The radiotracers were characterised and evaluated via in vivo imaging (MRI and SPECT/CT) and ex-vivo studies (phosphorimaging, biodistribution and metabolite analysis) in order to determine if they hold significant potential as tools to study neuronal pathways as well as for diagnostic imaging and treatment monitoring. Iodinated analogues of the iminodihydroquinoline WIN17317-3, and the 1-benzazepin-2-one BNZA have been evaluated as neuronal VGSC tracer candidates in healthy mice. Whilst the WIN17317-3 analogue suffered from poor brain uptake and was rapidly metabolised in vivo, the BNZA analogue exhibited excellent in vivo stability and its promising uptake in the brain warrants further investigations. Even though N-(1-Napthyl)-N’-(3-[123I]-iodophenyl)-N’-methylguanidine ([123I]CNS-1261) has demonstrated favourable pharmacokinetics for brain imaging in clinical studies, [125I]CNS-1261 was not successful in discriminating NMDAR expression between naïve rats and those induced with status epilepticus using lithium and pilocarpine. Promisingly, a multi modal contrast agent comprising micron sized particles of iron oxide conjugated to I-125 radiolabelled antibodies, highlighted the up-regulation of VCAM-1 in rat models of cerebral inflammation and in the lithium pilocarpine model of status epilepticus. This versatile imaging agent presents an exciting opportunity to identify an early biomarker for epileptogenesis.

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