Development of ⁶⁸Ga DOTA-CRH for PET/CT Imaging of ACTH-Dependent Cushing's Disease: Initial Study

Adrenocorticotropic hormone (ACTH)-dependent Cushing's disease accounts for 75% cases of the endogenous Cushing's syndrome. The size of lesion is usually very small, which results in false-negative magnetic resonance imaging (MRI) even after biochemical confirmation of the disease. Corticotrophin-releasing hormone (CRH) the key controller of hypothalamus-pituitary--adrenal axis binds to CRH receptor R1 and R2. CRH R1 is overexpressed in pituitary adenomas. The present study aims to target these overexpressed receptors with ⁶⁸Ga-DOTA-CRH for noninvasive imaging of ACTH-dependent pituitary adenomas. Custom-synthesized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-CRH peptide was purified by high performance liquid chromatography (HPLC) and characterized by mass spectra. Postradiolabeling optimization with ⁶⁸Ga, quality control tests were carried out to ensure the suitability of ⁶⁸Ga DOTA-CRH for intravenous administration. A pilot study consisting of 15 patients including 6 known cases of macroadenoma underwent ⁶⁸Ga-DOTA-CRH regional brain positron emission tomography/computed tomography (PET/CT). The optimal imaging time and biodistribution studies were performed in five patients' whole-body and serial brain PET/CT imaging. Lesion activity was determined as SUVmax and correlated with CE-MRI and histopathology of excised tissue. A retention time of 11.3 min and mass of 5145 Da was observed on HPLC and mass spectra. Radiolabeling yield of >98% was achieved under optimized conditions using 25-100 μg of conjugated peptide for 10-22 mCi of ⁶⁸Ga. The quality control results were in agreement with acceptable criteria. ⁶⁸Ga-DOTA-CRH was able to delineate ACTH secreting corticotropinoma in all 15 patients. Physiological uptake of radiotracer was observed in liver and spleen with diffused marrow activity. Excretion was noted by renal route. Imaging results were in correlation with CE-MRI and histopathology of excised tissue. ⁶⁸Ga-DOTA-CRH PET/CT is a promising molecular imaging modality for detection of ACTH-dependent microadenoma.