A newly developed PET imaging agent has been found to be effective in identifying medullary thyroid cancer (MTC) in preclinical and clinical studies, according to research published in the January issue of The Journal of Nuclear Medicine [1]. The results of the studies indicate that the PET imaging agent may be a promising theranostic candidate for clinical use.

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 labelled separately with 64Cu, 67Ga, and 177Lu. CCK-2R affinity of each of the radiolabelled compounds was examined on MTC cells. All three compounds exhibited a high affinity, however, due to the more favourable 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 tumour. 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 favourable biodistribution, and demonstrated high accumulation of activity in tumours.

“Due to increased in vivo stability, our compound reveals favourable tumour 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 commented: “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.”

Reference:
1. Günther T., Holzleitner N., Viering O. Preclinical Evaluation of Minigastrin Analogs and Proof-of-Concept [68Ga]Ga-DOTA-CCK-66 PET/CT in 2 Patients with Medullary Thyroid Cancer. Journal of Nuclear Medicine. January 2024, 65 (1).  doi: https://doi.org/10.2967/jnumed.123.266537