Medullary thyroid cancer (MTC) represents about 3% of all thyroid cancer cases and is notably rare. It arises from different cells compared to other thyroid cancers, necessitating distinct imaging and treatment approaches. The overexpression of the cholecystokinin-2 receptor (CCK-2R) on most MTC cells has led to the development of various compounds targeting this receptor. However, many of these compounds suffer from low metabolic stability, which hampers their effectiveness in radioligand therapy. Now, a newly developed PET imaging agent has shown promise in both preclinical and clinical studies for identifying MTC, suggesting its potential as a theranostic tool in clinical settings.

In a study conducted by researchers at Stanford University (Stanford, CA, USA), three compounds—DOTA-CCK-66, DOTA-CCK 66.2, and DOTA-MGS5—were each labeled with different isotopes: 64Cu, 67Ga, and 177Lu. The team evaluated the CCK-2R affinity of these radiolabeled compounds on MTC cells. All compounds displayed high affinity, but DOTA-CCK-66 was selected for further study due to its superior in vitro properties, leading to the exclusion of DOTA-CCK-66.2 from subsequent analyses.

Following this, the researchers carried out in vivo stability, biodistribution, imaging, and competition studies using mice with CCK-2R-expressing tumors. Based on its comprehensive in vitro and in vivo performance, 68Ga-DOTA-CCK-66 was chosen for a proof-of-concept PET/CT application. Subsequently, two MTC patients underwent 68Ga-DOTA-CCK-66 PET/CT scans. The scans revealed that the compound was well tolerated by the patients, exhibited favorable biodistribution, and demonstrated high activity accumulation in the tumors.

“Due to increased in vivo stability, our compound reveals favorable tumor uptake as well as an improved activity clearance from off-target tissues,” said Constantin Lapa, MD, director of nuclear medicine at University Hospital Augsburg. “This could result in enhanced lesion detection in PET imaging and additionally enable targeted MTC radioligand therapy.” 

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