Development of neurotransmitter-responsive MR and optical imaging probes
The growth of MRI smart contrast agents is in line with current directions in molecular imaging, and could have a substantial impact on our understanding of both normal cognitive function and neurological disorders at a fundamental level . The application of SCA whose signal varies as function of a given amino acid neurotransmitter allows us to investigate phenomena in any brain structure, as opposed to most fluorescence-based imaging methods, which are limited to depths of up to 1 mm.
The agents consist of lanthanide macrocyclic complexes conjugated to synthetic receptors for amino acids or mono amines, which change their magnetic properties in parallel with local concentrations changes of these neurotransmitters. Through the development of such agents, we aim to develop a technique to complement BOLD fMRI, to significantly increase the accuracy and specificity of non-invasive monitoring of neural activity.
Initially, the receptor site for these molecules was synthesised and linked to the reporter unit. Following their characterisation, the response of these complexes to a range of neurotransmitters was screened using NMR and luminescence spectroscopy. On obtaining a suitable and selective response their behaviour will be examined in a range of more competitive media including artificial cerebrospinal fluid. Ultimately, in vivo experiments in rats will be performed with the smart contrast agents exhibiting the most appropriate responses.
Two types of SCA were synthesized: on-agents that allow the approach of water molecules which increases MR signal and hence tissue contrast and off-agents that displace water molecules decreasing MR contrast. A series of 8 (phosphonate based) on agents and 3 (guanidine based) off agents were synthesized. The 3 off agents gave the best response to the addition of neurotransmitters, with a decrease in the MR signal (relaxivity r1). However, suitable selectivity was not demonstrated. Pyrrole guanidinium agents also responded to neurotransmitters, showing an interaction at the receptor site (Figure 1).
Off agents appear more effective than on agents. Therefore such systems will be developed further with more receptor sites to enhance selectivity.
1. Jasanoff A. (200) MRI contrast agents for functional molecular imaging of brain activity, Current Opinion in Neurobiology 17 593600.