Abstract
New and improved methods for introducing radioisotopic hydrogen (tritium) and carbon (positron-emitting short-lived carbon-11, t1/2 = 20.4 min) into organic molecules for application in biological research have been explored. In Chapter 1 the applications of radioactive isotopes in biological and clinical research is surveyed, with particular emphasis on the value of beta-emitting tritium and positron-emitting carbon-11. In Chapter 2 we report the use of the non-radioactive hydrogen isotope, deuterium, as a surrogate for tritium in the development of microwave-enhanced labelling procedures, based on catalytic hydrogen transfer to olefins (e.g. styrene, styrene derivatives, cinnamic acid and its derivatives). Hydrogen or deuterium donors (e. g. formate salts) were used alone or in combination with other sources (e. g. D2O). The method was found to give fully hydrogenated products using very short microwave irradiation times (~2 min) and was highly reproducible. Importantly, the method is environmentally clean, as when extended to tritiated formates little or no radioactive waste is produced. In Chapter 3 we explored the labelling of CGP 62349 {3-[1-(R)-[3-(4-methoxybenzyl)phosphinyl-2-(iS)-hydroxy-propyl-amino]ethyl]benzoic acid}, a gamma-aminobutyric acid type B (GABAB) receptor antagonist, with carbon-11 in order to provide a prospective radioligand for medical imaging with positron emission tomography (PET). Labelling agents, [11C]iodomethane and [11C]methyl triflate, prepared by improved methods, were used in the rapid methylation of desmethyl-CGP 62349. Substantially higher radiochemical yields (78%) of [11C]CGP 62349 were achieved by the new methods compared to that produced in a previously published procedure (9%). In addition, the use of [11C]methyl triflate rather than [11C]iodomethane has the advantage of giving a high radiochemical yield and a lower amount of carrier. In Chapter 4 we report on the use of [11C]carbon monoxide as a labelling agent. This has been done in two ways, namely by investigating, (i) the direct insertion of the carbonyl group into amines and (ii) by the palladium(II)-mediated cross coupling carbonylations of organostannanes with either aryl iodides or diaryliodonium salts. [11C]Carbon monoxide insertion into lithiated amines was found to be impractical. Palladium(II)-mediated cross coupling 11C-carbonylation was found to provide an efficient means to label substituted benzophenones. High radiochemical yields were achieved under very mild reaction conditions and in short reaction times (1 min). When various substituted diaryliodonium salts were used to partner phenyltributylstannane, the expected [11C]ketones were produced in moderate radiochemical yields (30 - 43%). By the use of variously substituted arylstannanes with diphenyliodonium bromide, several [11C]ketones were rapidly synthesised in exceptionally high radiochemical yields (typically 98%).