Development and clinical experience of [123/131I]IMAZA for theranostics of adrenocortical tumours

Aim 4-[123/131I]Iodometomidate (IMTO) selectively binds to the enzymes 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) and proved to be a valuable radiopharmaceutical for non-invasive classification of adrenocortical tissue, e.g. in diagnostic evaluation of adrenal incidentalomas and for treating metastatic adrenal carcinoma (ACC). Due to the low metabolic stability of IMTO, we preclinically evaluated numerous new derivatives and evaluated the most promising tracer in patients with metastatic ACC. Materials and Methods We synthesized over 80 new IMTO derivatives, replacing the labile methyl ester with other esters, amides and bioisosters. The inhibition of the two CYP11B enzymes was determined in murine Y1 cell lines. The most affine labelled substances were tested for metabolic stability in liver microsomes, in addition to cell uptake experiments and assessment of tracer binding to human cryosections. Subsequently biodistribution was evaluated in mice. Following a toxicity study, the most promising derivative was finally investigated in ACC patients. Results 17 new inhibitors exhibited potent enzyme inhibition. In vitro experiments showed comparable results to the reference compound IMTO. In animal experiments, the azetidinyl amide (IMAZA) emerged as the best candidate, demonstrating high and long-lasting uptake in the adrenals and lower toxicity than etomidate. Clinically, [123I]IMAZA showed a specific and long-lasting uptake in adrenocortical tissue. We observed rapid clearance of unbound tracer and an up to 5-fold higher tumour uptake compared to [123I]IMTO, significantly enhancing imaging quality. First patients received extremely high doses of up to 30 GBq [131I]IMAZA for endoradiotherapy, which were well tolerated. The selective and sustained uptake of [131I]IMAZA allowed tumour doses up to 265 Gy. Response assessment using RECIST 1.1 criteria in follow-up CT scans revealed stable disease in several patients. Conclusions We successfully developed an improved derivative of IMTO. The higher metabolic stability of IMAZA led to significantly improved imaging properties and increased therapeutic potential. Consequently, theranostics using [123/131I]IMAZA has become part of the clinical routine in our clinic.