Development of Signal Amplification By Reversible Exchange (SABRE) towards biological and forensic applications

Robertson, T. B. R (2019) Development of Signal Amplification By Reversible Exchange (SABRE) towards biological and forensic applications. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Work presented in this thesis focuses on the application of signal amplification by reversible exchange (SABRE) to the hyperpolarisation of small molecules. The aim of this work was to develop the technique towards future biologically relevant applications through resolution of barriers currently preventing clinical relevance. Furthermore, applications to forensics were also investigated. SABRE currently almost exclusively utilises iridium-based catalysts, however, there are reports of the utilisation of cobalt and one mixed iridium/rhodium system. A range of rhodium based complexes, [Rh(IMes)(COD)Cl] (6), [Rh(ImNPri2)(COD)Cl] (7), [Rh(ItBu)(COD)Cl] (8) and [Rh(ICy)(COD)Cl] (9), were synthesised and evaluated for SABRE activity. Testing demonstrated that these species were unable to form stable dihydride species at room temperature and therefore the iridium complex [Ir(IMes)(COD)Cl] (4) was utilised for the remainder of the work. 19F SABRE provides a versatile route for measurements in vivo due to the low background present within the body. This work assessed the hyperpolarisation of 2-, 3-, 4-, 3,5- and pentafluoropyridine (L2 – L6), that have been interrogated by SABRE to establish a theoretical understanding of their efficacy with respect to polarisation transfer. However, hyperpolarisation of L3, which yielded the highest enhancement, resulted in an antiphase signal which may lead to internal cancelation within a biological imaging context. Thus, Signal Amplification By Reversible Exchange in shield enables alignment transfer to heteronuclei (SABRE-SHEATH) was employed to generate an in-phase absorptive hyperpolarised signal. Recent studies have demonstrated 4 is cytotoxic, therefore the mounting of the catalyst on silica or polymer derived supports was evaluated for the generation of a HET-SABRE catalyst and hyperpolarisation reported for a heterogeneous system. The solids proved effective at scavenging the metal from solution, therefore, an evaluation of their potential efficacy for production of a biocompatible bolus following homogenous SABRE is presented. 2-(2-pyridyl)ethyl - functionalised silica gel (S5) is reported to be the most effective 4 metal scavenger utilised, with results suggesting ~1g of S5 is capable of reducing the iridium content of a bolus from ~1005ppm to below background levels within 2 minutes. The hyperpolarisation of a range of fentanyl derivatives is F1-F5, including Mirfentanil (F5), a derivative with known biological activity. Both F2 and F5 have been detected within an excess of heroin. F5 was detected at a concentration of 81 μM in ~5 seconds when ~145 mM of heroin was present. Further to this, the 19F SABRE of a world health organisation essential medicine, voriconazole, is reported at a concentration ~4 times below current dosing guidelines.