Synthesis and radiochemical stability evaluation of radiopharmaceutical compounds containing radioiodinated prosthetic groups

Rossouw, Daniel Du Toit (2004-12)

Thesis (PhD)--Stellenbosch University, 2004.

Thesis

ENGLISH ABSTRACT: A study was undertaken to investigate the radiochemical stability of the βiodoethoxyl moiety, a relatively novel prosthetic group employed in radiopharmaceutical chemistry, in which an oxygen atom in a β-position relative to the radioiodine atom has a stabilising effect on the aliphatic carbon-iodine bond. The investigation was started as a pilot study by synthesising various model compounds containing a β-radioiodoethoxyl moiety, as well as two reference compounds lacking such a moiety. The purpose was to determine the influence of various groups in the vicinity of the β-oxygen atom on the stability of the abovementioned moiety. Radiochemical stability tests were carried out in vitro at 37°C in human blood serum. The results confirmed the superior stability of such a moiety compared to that of the reference compounds and also showed that the branching of such an aliphatic unit resulted in a considerable improvement in its stability, especially over a longer period. The investigation was extended to the synthesis of other compounds containing a few selected β-iodoethoxyl moieties that showed improved stability in the pilot study work. Reference compounds containing the classical iodovinyl unit, as well as those lacking a stabilising β- oxygen atom, were also prepared. The carrier molecules used in this part of the work was a benzamide containing a phenolic oxygen atom which acted as the β-oxygen atom, as well as two heterocyclic amines, benzotriazole and 2-methyl-5-nitroimidazole, in which the β- iodoethoxyl moiety was linked to a secondary nitrogen atom. Various suitable alkylating agents were prepared, chemically linked to the carrier molecules, the resulting intermediate compounds converted into tosylate or triflate iodination precursors and labelled with radioiodine by means of iodide-for-tosylate/triflate exchange. In vitro stability tests of these compounds showed similar trends to those obtained with the model compounds. Moreover, the stability of the stabilised β-iodoethoxyl moiety compared favourably with that of the iodovinyl unit, especially when incorporated into a heterocyclic amine. The results of this study have shown that some of the radioiodinated compounds synthesized in this work, especially the nitroimidazole derivatives, have the potential to be considered as novel radiopharmaceuticals.

AFRIKAANSE OPSOMMING: 'n Studie is onderneem om die radiochemiese stabiliteit van die β-jodium-etoksi-eenheid te ondersoek. Dié eenheid is 'n relatief nuwe prostetiese groep wat in radiofarmaseutiese chemie gebruik word. Die suurstofatoom wat in 'n β-posisie relatief tot die radiojodiumatoom voorkom, oefen 'n stabiliserende invloed op die alifatiese koolstof-jodiumbinding uit. Die ondersoek het met 'n loodsstudie begin deur verskillende modelverbindings te sintetiseer wat 'n β-radiojodium-etoksi-eenheid bevat, asook twee verwysingsverbindings waarin so 'n eenheid ontbreek. Die doel hiermee was om die invloed van verskillende groepe, wat in die omgewing van die β-suurstofatoom voorkom, op die stabiliteit van die eenheid te bepaal. Radiochemiese stabiliteitstoetse is uitgevoer deur middel van inkubering in menslike bloedserum by 37°C. Die resultate het die groter stabiliteit van so 'n eenheid in vergelyking met dié van die verwysingsverbindings aangetoon, en het ook uitgewys dat vertakking van so 'n alifatiese eenheid 'n aansienlike verbetering in die stabiliteit tot gevolg gehad het, veraloor 'n langer periode. Die ondersoek is vervolgens uitgebrei deur verdere verbindings te sintetiseer wat beskik oor bepaalde uitgesoekte β-jodium-etoksi-eenhede, wat verbeterde stabiliteit in die loodsstudie getoon het. Verwysingsverbindings wat die klassieke jodiumvinieleenheid bevat het, sowel as dié waarin 'n stabiliserende β-suurstofatoom ontbreek het, is ook berei. Die draermolekules wat in hierdie deel van die studie gebruik is, was 'n bensamied met 'n fenoliese suurstofatoom wat as die β-suurstofatoom gedien het, sowel as twee heterosikliese amiene, bensotriasool en 2- metiel-5-nitroimidasool, waarin die β-jodium-etoksi-eenheid aan 'n sekondêre stikstofatoom geheg is. Verskillende geskikte alkileermiddels is berei, aan die draermolekules geheg, die tussenprodukte omskep in tosilate of triflate en met radiojodium gemerk deur middel van jodium-vir-tosilaatltriflaat-uitruiling. Stabiliteitstoetse van hierdie verbindings in bloedserum het soortgelyke tendense as dié van die aanvanklike modelverbindings getoon. Daarbenewens het die stabiliteit van die gestabiliseerde β-jodium-etoksi-eenheid gunstig vergelyk met dié van die jodiumviniel-eenheid, veral wanneer dit deel gevorm het van 'n heterosikliese amien. Die resultate van die studie het getoon dat sommige van die radiogejodeerde verbindings wat berei is, veral die nitroimidasoolderivate, die potensiaal het om as nuwe radiofarmaseutiese verbindings gebruik te kan word.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/50113
This item appears in the following collections: