The development of novel PET imaging agents for the poly(ADP-ribose) polymerase 1 and synaptic vesicle 2A proteins

The primary focus of this PhD research was the development and synthesis of several potential PET imaging agents for the PARP-1 and SV2A proteins. The first section of this thesis details the synthesis of a small library of novel PARP-1 inhibitors (HM library) with capacity for application as PET imaging agents. The core structure of these compounds was that of established PARP-1 inhibitor olaparib and was modified with a novel linker to allow incorporation of aromatic units that could undergo late-stage radiolabelling. The physicochemical properties of this library were determined via HPLC methodology and subsequently, four candidates were submitted to in vitro biological testing of PARP-1 inhibition. Finally, an initial optimisation study for the radiosynthesis of a novel fluorine-18 PET imaging agent for PARP-1 was conducted. The second section describes a new six-step racemic synthesis of [18F]MNI-1038 an established PET imaging agent for the SV2A protein via an organotin precursor, and the fluorine-19 equivalent. Modification of this route and utilisation of asymmetric iminium organocatalysis facilitated the first enantioselective synthesis of the important PET radiotracer [18F]SynVesT-1 in eight steps, and the corresponding fluorine-19 analogue. The final section describes the exploration of two novel transition metal catalysed methods for the transformation of ubiquitous phenols via aryl nonafluorobutanesulfonates. Firstly, a new ruthenium-catalysed reaction for the iodination of arenes was examined. This study produced some promising results and demonstrated the potential for application of this methodology in the synthesis of SPECT imaging agents. Subsequently, a novel sodium iodide-accelerated, palladium-catalysed reaction was developed for the construction of aryl C‒P bonds. The synthetic utility of this methodology was then exemplified through the synthesis of various organophosphorus compounds including triarylphosphine oxides, dialkyl arylphosphine oxides, aryl phosphonates and an aryl phosphinate. Furthermore, this reaction was employed for the synthesis of an organic light emitting diode (OLED) material and a phosphonophenylalanine mimic with applications in medicinal chemistry

Ligand-enabled copper-mediated radioiodination of arenes

The discovery of a copper precatalyst that facilitates the key mechanistic steps of arene halodeboronation has allowed a step change in the synthesis of radioiodine-containing arenes. The active precatalyst [Cu(OAc)(phen)2]OAc was shown to perform room temperature radio-iododeboronation of aryl boronic acids with 1–2 mol % loadings and 10 min reaction times. These mild conditions enable particularly clean reactions, as demonstrated with the efficient preparation of the radiopharmaceutical and SPECT tracer, meta-iodobenzylguanidine (MIBG).Peer reviewe

Palladium-catalyzed C—P bond-forming reactions of aryl nonaflates accelerated by iodide

An iodide-accelerated, palladium-catalyzed C–P bond-forming reaction of aryl nonaflates is described. The protocol was optimized for the synthesis of aryl phosphine oxides and was found to be tolerant of a wide range of aryl nonaflates. The general nature of this transformation was established with coupling to other P(O)H compounds for the synthesis of aryl phosphonates and an aryl phosphinate. The straightforward synthesis of stable, isolable aryl nonaflates, in combination with the rapid C–P bond-forming reaction allows facile preparation of aryl phosphorus target compounds from readily available phenol starting materials. The synthetic utility of this general strategy was demonstrated with the efficient preparation of an organic light-emitting diode (OLED) material and a phosphonophenylalanine mimic

Recent advances in synthetic methods for radioiodination

Organic compounds bearing radioisotopes of iodine are widely used for biological research, diagnostic imaging, and radiotherapy. Early reported synthetic methods for the incorporation of radioiodine have generally involved high temperature reactions or strongly oxidizing conditions. To overcome these limitations and to cope with the demand for novel radioiodinated probes, there has been a surge in the development of new synthetic methodology for radioiodination. This synopsis describes the key transformations developed recently

Ligand-enabled copper-mediated radioiodination of arenes

The discovery of a copper precatalyst that facilitates the key mechanistic steps of arene halodeboronation has allowed a step change in the synthesis of radioiodine-containing arenes. The active precatalyst [Cu(OAc)(phen)2]OAc was shown to perform room temperature radio-iododeboronation of aryl boronic acids with 1–2 mol % loadings and 10 min reaction times. These mild conditions enable particularly clean reactions, as demonstrated with the efficient preparation of the radiopharmaceutical and SPECT tracer, meta-iodobenzylguanidine (MIBG).</div

Organocatalytic asymmetric synthesis of SynVesT-1, A synaptic density PET imaging agent

No abstract available