Novel PET tracer enhances lesion detection in medullary thyroid cancer, offers potential for targeted therapy

MTC is one of the rarest forms of thyroid cancer and accounts for approximately three percent of all cases. Since MTC originates from different cells than most thyroid cancers, different imaging and therapy targets are needed for these patients.

"The cholecystokinin-2 receptor (CCK-2R) is overexpressed on most MTC cells and various compounds targeting CCK-2R have been developed over the past several years. Most of these compounds, however, have low metabolic stability, which is not ideal for radioligand therapy," noted Thomas Günther, PhD, pharmaceutical radiochemist at Stanford University in Stanford, California. "With a simplistic design modification to tackle instability issues, our team created multiple theranostic agents and sought to evaluate their effectiveness."

In the study, three compounds (DOTA-CCK-66, DOTA-CCK 66.2, and DOTA-MGS5 external reference]) were each labeled separately with ⁶⁴Cu, ⁶⁷Ga, and ¹⁷⁷Lu. CCK-2R affinity of each of the radiolabeled compounds was examined on MTC cells. All three compounds exhibited a high affinity, however, due to the more favorable in vitro properties overall of DOTA-CCK-66, DOTA-CCK-66.2 was excluded from further studies.

Next, in vivo stability, biodistribution, imaging, and competition studies were performed on mice bearing a CCK-2R-expressing tumor. ⁶⁸Ga-DOTA-CCK-66 was selected for proof-of-concept PET/CT application based on its overall in vitro and in vivo properties.

Two MTC patients then underwent ⁶⁸Ga-DOTA-CCK-66 PET/CT. The compound was well tolerated, showed a favorable biodistribution, and demonstrated high accumulation of activity in tumors.

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

Günther and Lapa added, "A significant outcome of our work is the notion that it is possible to optimize pharmacokinetics by chemical design. Analyzing weaknesses of existing compounds and then systematically addressing those to improve imaging and treatment is crucial for future clinical translation."

This research was published online in November 2023.

The authors of "Preclinical Evaluation of Minigastrin Analogs and Proof-of-Concept [⁶⁸Ga]Ga-DOTA-CCK-66 PET/CT in 2 Patients with Medullary Thyroid Cancer" include Thomas Günther, Nadine Holzleitner, Roswitha Beck, and Hans-Jürgen Wester, Department of Chemistry, Chair of Pharmaceutical Radiochemistry, TUM School of Natural Sciences, Technical University of Munich, Garching, Germany; and Oliver Viering, Georgine Wienand, Alexander Dierks, Christian H. Pfob, Ralph A. Bundschuh, Malte Kircher, and Constantin Lapa, Nuclear Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany.