Metabolically stabilised radiotracers for the diagnosis of adrenocortical tumours and radiotherapy of adrenal carcinoma

• Published in: Experimental and Clinical Endocrinology & Diabetes
• Main Authors: Heinze, B, Schirbel, A, Thomas, E, Göbel, H, Zink, M, David, M, Nannen, L, Ries, M, Allolio, B, Hahner, S
• Format: Conference Proceeding
• Language: English
• Published: 07.03.2013
• ISSN: 0947-7349; 1439-3646
• DOI: 10.1055/s-0033-1336615

Objective: We have recently developed [ 123/131 I]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 11ß-hydroxylase (CYP11B1). The tracer is rapidly metabolised both in vitro and in vivo by hepatic esterases. Due to the low metabolic stability of IMTO, our aim was to develop specific radiotracers with improved metabolic stability. Methods: More than 80 new IMTO derivatives were designed. The unstable methyl ester was replaced by other esters, amides and bioisosteres. The inhibition of aldosterone/cortisol was tested in murine Y1 cells expressing human CYP11B1/CYP11B2. Radiosynthesis of the most promising compounds with high affinity to both enzymes was established and their stability was determined by radio-HPLC after incubation with liver microsomes. In addition, intracellular uptake was determined in human adrenocortical NCI-H295 cells and biodistribution in male CD1 mice was analysed. Results: 17 IMTO analogues with high affinity binding to the target enzymes, mostly aliphatic esters and tertiary amides, exhibited equal or even better metabolic stability compared to IMTO. These new radiotracers also showed high specific intracellular accumulation, comparable or significantly higher compared to the reference substance IMTO. In particular, the amides exhibited high, lasting and highly specific uptake in the adrenal gland in biodistribution experiments. Conclusion: We have successfully developed new radiotracers with comparable or even better binding properties and favourable metabolic stability. These compounds may be suitable for nuclear medicinal diagnostics and particularly helpful for radiotherapy of adrenocortical carcinoma due to their highly specific and lasting uptake in the target tissue.