Electron-Affillic Compounds for Labelling Hypoxie Cells : The Synthesis and Characterization of 1-[2-(2-Iodophenoxy)-Ethyl]-2-Nitroimidazole^[*]

Summary

Highly lipophilic and proteinbound derivatives of l-(2-phenoxyethyl)-2-nitroimidazole (PENI; RGW609), a known radiosensitizer, have been prepared by introducing one (IPENI) and two (DIPENI) iodine atoms into the phenyl ring via electrophilic substitution. The electron affinity of all 3 compounds, as determined by differential pulse polarography, was similar to that for MISO, a radiosensitizer which has undergone clinical trial, but P values were 2-3 orders of magnitude greater that for MISO and %PB values were as high as 30% in vitro compared to less than 1% for MISO. ¹³¹I-PENI was prepared by catalysed halogen exchange with Na¹³¹I in greater than 90% yield, and was found to be chemically and radiochemically stable in solution for at least 2 weeks. Whole-body studies in BDF/1 mice bearing EMT-6 tumors showed rapid hepatic extraction and biliary elimination with little or no accumulation in any other tissue including tumor and fat, indicating that P and %PB values had little impact on in vivo distribution and disposition. ¹³¹I-PENI was not measurably deiodinated in vivo. IPENI and DIPENI are radiosensitizers by inference only, that is, they have not been tested for radiosensitizer properties. However, PENI, the parent compound, has been shown to be active as a radiosensitizer, and the peak potentials (polarographic) for both IPENI and DIPENI fall near those of MISO, PENI and most other 2-nitroimidazole sensitizers. The low levels of concentration in target tissues achieved by ¹³¹I-PENI mitigate against its use as a diagnostic agent. Metabolic and pharmacokinetic studies, as well as an investigation of their radiosensitizing properties are required to determine whether IPENI or DIPENI have the potential to be used therapeutically.

Zusammenfassung

Stark lipophile und proteingebundene Derivate von l-(2-phenoxy-äthyl)-2-nitroimidazol (PENI, RGW-609), einem bekannten Radiosensibilisator, wurden dargestellt, indem ein (IPENI) oder zwei (DIPENI) Jodatome in den Phenylring durch elektrophile Substitution eingeführt wurden. Die Elektroaffinität von allen drei Verbindungen, bestimmt durch Differential-Puls-Polarographie, war ähnlich der von MISO, einem Radiosensibilisator, der einer klinischen Erprobung unterzogen wurde; die PWerte waren jedoch 2-3 Größenordnungen höher als die von MISO und die %PD-Werte betrugen 30% in vitro verglichen mit 1% für MISO. ¹³¹J-PENI wurde durch katalysierten Halogenaustausch mit Na ¹³¹J mit einer Ausbeute von mehr als 90% präpariert und war in Lösung mindestens 2 Wochen lang chemisch und radiochemisch stabil. Ganzkörperstudien in EMT-6 tumortragenden BDF/1 Mäusen zeigten eine rasche hepatobiliäre Ausscheidung und eine nur geringe oder keine Anreicherung in anderen Geweben einschließlich Tumor und Fett; die Pund %PD-Werte haben somit wenig Einfluß auf die In-vivoVerteilung. ¹³¹J-PENI wurde in vivo nicht meßbar dejodiniert. IPENI und DIPENI sind Radiosensibilisatoren lediglich aufgrund eines Analogieschlusses, d.h., die radiosensibilisierenden Eigenschaften wurden nicht getestet. Die Mutterverbindung PENI erwies sich jedoch als aktiver Radiosensibilisator und die polarographischen Spitzenpotentiale sowohl für IPENI wie auch DIPENI kommen nahe an die von MISO, PENI und die der meisten anderen 2-nitro-imidazol-Sensibilisatoren. Die niedrigen Konzentrationen, die von ¹³¹J-PENI im Zielgewebe erreicht werden, sprechen gegen eine Anwendung als Diagnostikum. Metabolische und pharmakokinetische Untersuchungen sind ebenso erforderlich wie eine Überprüfung ihrer Eigenschaften als Radiosensibilisatoren, um entscheiden zu können, ob IPENI und DIPENI möglicherweise therapeutisch eingesetzt werden können.

^* 3rd International Symposium on Radiopharmacology, Freiburg i.Br., September 1983.

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