Rationale: Myocardial infarction (MI) is one of the leading causes of death worldwide and inflammation is central to the tissue response and patient outcomes. The 18kDa translocator protein (TSPO) has been utilized in positron emission tomography (PET) as an inflammatory biomarker. The aims of this study were to: 1) screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart, 2) assess whether the in vivo characteristics of our lead radiotracer, 18 F-LW223, are suitable for clinical translation and 3) validate whether 18 F-LW223 can detect macrophage driven inflammation in a rat myocardial infarction model. Methods: Fifty-one human brain and twenty-nine human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3 H-PK11195 and the following ligands: PK11195, PBR28 and our novel compounds (AB5186 and LW223). Naive rats and mice were used for in vivo PET kinetic studies, radiometabolite studies and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with invasive input function at 7 days following MI. For quantification of PET signal in the hypoperfused myocardium, K 1 was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BP TC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18 F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (62% of parent at 120 min), a high plasma free fraction of 38.5% and a suitable dosimetry profile Brain Tissue for Binding Assays Heart Tissue for Binding Assays

An investigation into the mechanism of Cu-catalyzed aryl boronic acid halodeboronation using electrophilic halogen reagents is reported. Evidence is provided to show that this takes place via a boronate-driven ipso-substitution pathway and that Cu is not required for these processes to operate: general Lewis base catalysis is operational. This in turn allows the rational development of a general, simple, and effective base-catalyzed halodeboronation that is amenable to the preparation of 125 I-labeled products for SPECT applications.

An operationally simple, one-pot, two-step tandem procedure that allows the incorporation of radioactive iodine into aryl amines via stable diazonium salts is described. The mild conditions are tolerant of various functional groups and substitution patterns, allowing latestage, rapid access to a wide range of 125 I-labelled aryl compounds and SPECT radiotracers.

Palladium(II)-catalysed cycloalkenylation (Saegusa-Ito cyclisation) has been used for the first time to transform difluorinated silylenol ethers to difluorinated cycloalkenones under mild conditions. The silylenol ether precursors were prepared in two high-yielding steps from trifluoroethanol, and cyclised in moderate to good yields. A combination of air and copper(I) chloride in acetonitrile gave the turnover of the initial palladium(II) salt, whereas the provision of an oxygen atmosphere ensured more rapid reaction. Annulations required a minimum level of substitution on the chain, but failed when the alkene was substituted. Annelations allowed a range of n,6-bicyclic systems to be prepared and afforded three products, in which heterocycles were fused to the new cyclohexenone. The least substituted system explored underwent cyclisation followed by terminal oxidation to a cyclic enal, which corresponded to a Wacker product of unusual regiochemistry.

A tandem process has been developed for the general preparation of aryl iodide compounds from anilines that is also applicable for the late-stage iodination of biologically active agents.