Modified Desmopressin (Mdesmo Cold-Kit) for PET Imaging to Localize Adrenocorticotropic Hormone (ACTH) Dependent Cushing Syndrome (CS)

The incidence of Cushing syndrome (CS) is 1.2-3.2 cases per million per year, of which adrenocorticotropic Hormone (ACTH)-dependent disease comprises approximately 70-80% of cases. Among these, nearly 90% of ACTH-dependent CS are due to pituitary-dependent CS, known as Cushing disease (CD). The management of ACTH-dependent CS relies on distinguishing Cushing disease (or Corticotropinoma) from ectopic Cushing syndrome (ECS) followed by localization of the tumor in the sella. The diagnosis of CD is very challenging, especially when they are microadenomas (<6 mm). Current imaging techniques, such as magnetic resonance imaging (MRI), have limitations in accurately delineating (sensitivity 60%) these tumors. Even if the lesion is detected inside the pituitary, the functionality of the tumor is questionable, as there can be innocent pituitary tumors which actually are not the cause of Cushing syndrome in a particular case. The diagnosis gets more complex with the fact that 10% of the ECS cases are reported to have an incidental non-functioning pituitary tumor, this can complicate the diagnosis of ECS. Though the localizing accuracy of bilateral inferior petrosal sinus sampling (BIPSS) is 90%, the lateralization (40-70%) of corticotropinoma (whether the lesion is located on the right or left side) based on BIPSS is still questionable. These challenges contribute to the fact that in approximately 30% of cases of CD, the source of ACTH excess remains occult. The lack of information on accurate localization and lateralization of corticotropinoma leads to reduced remission rates after surgery. Therefore, novel approaches to diagnosing Cushing disease are needed.

We have developed a novel radiopharmaceutical Gallium-68- 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid-modified desmopressin (68Ga-DOTA-mDesmo) for Positron Emission Tomography/Computed Tomography (PET/CT). This radiopharmaceutical has the potential to selectively target the overexpressed V1b receptors in patients diagnosed with Cushing disease. The clinical studies demonstrated 100% diagnostic accuracy of 68Ga-DOTA-mDesmo PET/CT in delineating corticotropinomas, surpassing the accuracy of CE-MRI and BIPSS, regardless of adenoma size. However, the small sample size and regional patient recruitment may affect the generalizability of the results.

The project aims to assess the diagnostic sensitivity and specificity of 68Ga-DOTA-mDesmo in a diverse Cushing syndrome population. This will lead to development and validation of a superior, non-invasive diagnostic modality for accurate corticotropinoma delineation, aiding neuro-navigation during surgery and potentially improving treatment outcomes for ACTH-dependent Cushing syndrome.