ECE2014 Poster Presentations Adrenal cortex (56 abstracts)
Development of new improved derivatives of iodometomidate for the diagnosis of adrenocortical tumours and radiotherapy of adrenal carcinoma
Britta Heinze 1 , Andreas Schirbel 2 , David Michelmann 1 , Lukas Nannen 1 , Martin Ries 1 , Elke Thomas 2 , Heike Göbel 2 , Bruno Allolio 1 & Stefanie Hahner 1
1Endocrinology and Diabetes Unit, Department of Internal Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany; 2Department of Nuclear Medicine, University Hospital of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.
Objective: We have developed (123/131I)iodometomidate (IMTO) for specific adrenal imaging and radiotherapy of adrenocortical carcinoma. IMTO binds with high affinity and specificity to the two adrenocortical enzymes aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11B1). Metabolic analysis has revealed very rapid metabolization of IMTO both in vitro and in vivo by hepatic esterases. Due to the low metabolic stability of (123/131)IMTO we have developed new stabilised radiotracers in order to improve specificity and therapeutic efficacy.
Methods: We have developed more than 90 IMTO derivates in which the metabolic labile methyl esters were replaced by other esters, amides, or bioisosteres, respectively. The inhibition of aldosterone/cortisol was tested in murine Y1 cells expressing human CYP11B1/CYP11B2. Radiosynthesis of the 16 compounds with the highest affinity to both enzymes was established and stability was determined by radio-HPLC after coincubation with liver microsomes. In addition, intracellular uptake was determined in human adrenocortical NCI-H295 cells and biodistribution in male CD1 mice was analyzed.
Results: 16 IMTO analogues especially the aliphatic esters and tertiary amides showed comparable or better enzyme binding than IMTO. These new radiotracers showed also high specific intracellular accumulation comparable to the reference substance (123/131I)IMTO in NCI-H295 cells. In animal experiments particularly the amides showed an extremely high and impressively specific uptake in the adrenal gland. One candidate showed a tenfold higher uptake than (125I)IMTO in the adrenal gland of CD1 mice 240 min after injection and <1% ID/g tissue in all other organs.
Conclusion: We have successfully developed many new radiotracers with comparable or even better binding properties and superior metabolic stability than (123/131I)iodometomidate. These compounds may be suitable for nuclear medicinal diagnostic and radiotherapy of adrenocortical carcinoma.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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