Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Angiotensin converting enzyme (ACE), a dipeptidyl carboxypeptidase, is one of the enzyme components of the renin-angiotensin-aldosterone system. ACE is responsible for the production of angiotensin II, a potent vasoconstrictor, and for the inactivation of the potent vasodepressor peptide bradykinin. The enzyme is a vascular endothelial component of many tissues (i.e. lungs, kidney, preoptic region of brain) and has been shown to be localized on the lumenal surface of the vascular endothelium. Diseases involving granuloma (i.e. sarcoidosis, silicosis, asbestosis) are known to change the distribution of ACE and to cause hypertension. A radiolabelled pharmaceutical which binds with ACE could permit the in vivo assessment of the distribution of ACE, with a possible correlation to endothelial integrity. It is proposed that iodine labelled analogues of ACE inhibitors could have potential as ACE imaging agents.;Captopril ( ((S)-3-mercapto-2-methyl-oxopropyl) -L-proline) is an ACE inhibitor which is used therapeutically in the treatment of hypertension. Work towards ((S)-3-mercapto-2-methyl-oxopropyl) -4-iodopyrrole-2-carboxylic acid is discussed along with why this compound was abandoned due to hydrolysis of the amide bond.;Lisinopril (N{dollar}\sp{lcub}\alpha{rcub}{dollar}-((S)-1-carboxy-3-phenylpropyl)-L-lysyl-L-proline) is another therapeutically used ACE inhibitor. An N{dollar}\sp{lcub}\varepsilon{rcub}{dollar}-3-iodobenzoyl derivative has been prepared and was found to have an IC{dollar}\sb{lcub}50{rcub}{dollar} of 6 {dollar}\times{dollar} 10{dollar}\sp{lcub}-10{rcub}{dollar} {dollar}\pm{dollar} 1 {dollar}\times{dollar} 10{dollar}\sp{lcub}-10{rcub}{dollar} M. Biodistribution studies in CD-1 mice carried out with ({dollar}\sp{lcub}131{rcub}{dollar}I) -N{dollar}\sp{lcub}\alpha{rcub}{dollar}-((S)-1-carboxy-3-phenylpropyl)-{dollar}{lcub}\rm N{rcub}\sp{lcub}\varepsilon{rcub}{dollar}-(3-iodobenzoyl)-L-lysyl-L-proline illustrate specific uptake in the lung and kidney. An imaging study carried out in a rabbit shows the potential of this compound as an imaging agent.;Work towards N{dollar}\sp{lcub}\alpha{rcub}{dollar}-((S)-1-carboxy-3-(4-iodophenyl)propyl-L-lysyl-L-proline), another Lisinopril analogue, is also reported.



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