Pandey Somit, Walia Rama, Kaur Gurvinder, Pandav Kumud, Rather Imran, Rana Nivedita, Sahoo Sushant, Mittal Bhagwant Rai, Shukla Jaya
Department of Nuclear Medicine, Post Graduate Institute of Medical Education & Research (P.G.I.M.E.R), Chandigarh, India.
Department of Endocrinology, Post Graduate Institute of Medical Education & Research (P.G.I.M.E.R), Chandigarh, India.
Commun Med (Lond). 2025 Aug 22;5(1):367. doi: 10.1038/s43856-025-01033-z.
Cushing's disease, the most common cause of Cushing's syndrome, is driven by pituitary tumors (corticotropinoma) and characterized by the overexpression of CRH R1 and V1b receptors. Accurate detection of these tumors remains challenging. This study aims to develop and evaluate a corticotropinoma specific radiopharmaceutical, [Ga]Ga-DOTA-mDesmo, that targets the V1b receptor for both anatomical and functional identification of corticotropinomas.
Molecular docking was used to validate the binding affinity of [Ga]Ga-DOTA-mDesmo to the V1b receptor. Radiolabeling was optimized with gallium-68, followed by quality controls and physicochemical characterization. ACTH-release assay was performed using primary-cultured corticotropinoma cells. Receptor specificity was confirmed via radioimmunoassay using recombinant human V1b receptor. Ex vivo biodistribution studies were performed in healthy male Wistar rats at 30-, 60-, and 120-min post-injection (8 ± 1.1 MBq).
Here we show that [Ga]Ga-DOTA-mDesmo binds effectively to the V1b receptor, with a binding energy of -13.98 kcal/mol and the key interacting residues of V1b are GLN301, SER304, ASN309, and ASP314. Radiolabeling achieves high yield (~96%) and purity (>99%), with human serum stability for up to 4 h. In vitro studies confirm that DOTA-mDesmo acts as an agonist in corticotropinoma cells. Excess cold DOTA-mDesmo results in a 50% blocking in binding. Biodistribution in rats indicates renal clearance, with high %ID/g in the kidneys (7.37 ± 0.58) and urinary bladder (4.32 ± 0.48), and negligible uptake in the pituitary gland, our organ of interest.
These finding support [Ga]Ga-DOTA-mDesmo as a promising radiotracer for non-invasive, receptor-targeted PET/CT imaging of corticotropinomas in patients with Cushing's disease.
库欣病是库欣综合征最常见的病因，由垂体肿瘤（促肾上腺皮质激素瘤）引起，其特征为促肾上腺皮质激素释放激素受体1（CRH R1）和血管活性肠肽受体1b（V1b受体）过表达。准确检测这些肿瘤仍然具有挑战性。本研究旨在研发并评估一种针对促肾上腺皮质激素瘤的特异性放射性药物[镓-68]Ga-DOTA-mDesmo，该药物靶向V1b受体，用于促肾上腺皮质激素瘤的解剖学和功能鉴定。
采用分子对接来验证[镓-68]Ga-DOTA-mDesmo与V1b受体的结合亲和力。用68Ga对放射性标记进行优化，随后进行质量控制和理化特性表征。使用原代培养的促肾上腺皮质激素瘤细胞进行促肾上腺皮质激素释放试验。通过使用重组人V1b受体的放射免疫测定来确认受体特异性。在健康雄性Wistar大鼠注射后30分钟、60分钟和120分钟（8±1.1 MBq）进行离体生物分布研究。
我们在此表明，[镓-68]Ga-DOTA-mDesmo与V1b受体有效结合，结合能为-13.98 kcal/mol，V1b的关键相互作用残基为GLN301、SER304、ASN309和ASP314。放射性标记产率高（约96%）且纯度高（>99%），在人血清中稳定性长达4小时。体外研究证实，DOTA-mDesmo在促肾上腺皮质激素瘤细胞中起激动剂作用。过量的冷DOTA-mDesmo导致结合被阻断50%。大鼠体内生物分布表明通过肾脏清除，肾脏（7.37±0.58）和膀胱（4.32±0.48）中的每克注射剂量百分摄取率（%ID/g）较高，而我们感兴趣的器官垂体的摄取可忽略不计。
这些发现支持[镓-68]Ga-DOTA-mDesmo作为一种有前景的放射性示踪剂，用于库欣病患者促肾上腺皮质激素瘤的非侵入性、受体靶向PET/CT成像。
