Mulligan, Rachel Suzanne; (2001) Chemical and analytical aspects of radioligand development for quantitative neuroimaging. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Recently, SPET neuroimaging has progressed from simple empirical methods of analysis to more sophisticated quantitative methods for determining receptor-radioligand binding parameters, such as binding potential. In this thesis, different aspects of radioligand development were investigated in support of quantitative SPET neuroimaging; these include the preparation of precursors for new improved radioligands, optimisation of radiolabelling and radiochemical purity, evaluation and control of radiochemical stability and accurate measurement of radioactive metabolites in plasma (to provide an accurate input function for biomathematical modelling). It was shown that the 5-HT2A receptor radioligand, [123I]5-iodo-R91150 ([123I]5-iodo-4-amino- N-[l-3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-2-methoxybenzamide), was cleared rapidly from blood and plasma in humans. Very low peripheral metabolism was observed. All four detected radioactive metabolites were more polar than 5-iodo-R91150. However, the radiochemical purity of the dose had a significant impact on the measurement of the fraction of radioactivity representing unchanged radioligand in plasma. The synthesis of precursors for potentially new radioligands for the 5-HT2A receptor, based on R91150 as a lead compound, was attempted. The synthesis of a key intermediate, l-[3-(4- fluorophenoxy)propyl]4-methyl-4-piperidinamine, was significantly improved. Its coupling to 4- amino salicylic acid failed to give one target precursor, 4-amino-N-[l-3-(4-fluorophenoxy)propyl]-4- methyl-4-piperidinyl]-2-hydroxybenzamide. Model coupling reactions, using 1-methyl cyclohexylamine and various analogues of 4-amino salicyclic acid, were performed. These indicated the need to protect the phenol and amino groups in 4-amino salicylic acid. The presence and position of these groups, in addition to the carboxyl group, prevented easy protection. The D2 receptor radioligand, [123I]epidepride ([123I)(S)-N-((ethyl-2-pyrrolidinyl)methyl)-5-iodo-2,3-dimethoyoxybenzamide), was prepared from (S)-5-(tri-n-butyltin)-N-[(l-ethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxybenzamide or its rn-methyltin analogue. The m-butylstannyl precursor gave a high percentage of an unidentified and difficult to separate radioactive impurity. However, m-methylstannyl precursor gave radiochemically pure [123I]epidepride. This radioligand was rapidly metabolised to 5 radioactive compounds in vivo. A high degree of inter-individual variation in results was observed, especially with respect to the level of a radioactive lipophilic metabolite.

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