Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, 97080, Wuerzburg, Germany.
Department of Nuclear Medicine, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, D-97080, Wuerzburg, Germany.
Eur J Nucl Med Mol Imaging. 2021 Dec;49(1):301-310. doi: 10.1007/s00259-021-05477-y. Epub 2021 Jul 3.
Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [I]iodometomidate ([I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers.
Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [I]IMTO and the most promising compound (R)-1-[1-(4-[I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [I]IMAZA in one of these patients was performed.
We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy.
We developed the new radiopharmaceutical [I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.
肾上腺肿瘤是一个诊断和治疗上的挑战。通过针对细胞色素 P450 酶 CYP11B1 和 CYP11B2 进行分子成像，已经取得了有希望的结果，并且碘米托咪醇 ([I]IMTO) 甚至已经成功地被引入作为一种治疗药物。由于这种放射性药物表现出快速的代谢失活，我们旨在开发新的改进示踪剂。
通过用不同的羧酸酯或酰胺取代不稳定的甲酯，新设计了几种 IMTO 衍生物。在不同的肾上腺皮质细胞系中测试了它们对醛固酮和皮质醇合成的抑制作用。评估了相应的放射性标记化合物的稳定性、体外细胞摄取、在小鼠体内的生物分布以及它们与人类肾上腺皮质和非肾上腺皮质组织冷冻切片的结合特异性。此外，在已知患有转移性肾上腺癌的患者中，使用 [I]IMTO 和最有前途的化合物 (R)-1-[1-(4-[I]碘代苯基)乙基]-1H-咪唑-5-羧酸氮杂啶酰胺 ([I]IMAZA) 进行了闪烁显像的首次研究。随后，在其中一名患者中进行了首次 [I]IMAZA 的内放射治疗。
我们鉴定了三种与靶酶具有高亲和力结合的 IMTO 类似物，它们具有相似或更高的代谢稳定性，并且在体外和体内对肾上腺皮质细胞具有非常高和特异性的积累。与 IMTO 相比，标记的 IMAZA 在小鼠和 3 名患者中表现出更好的药代动力学和成像特性。在这种治疗之前，一名患有快速进展的 ACC 的患者接受了 [I]IMAZA 的内放射治疗，诱导了 21 个月的无进展间隔期。
我们开发了新的放射性药物 [I]IMAZA，与参比化合物 IMTO 相比具有更好的特性，并在人类中获得了有前途的初步经验。
