It is difficult to quantify the sea of change that advancements in medical imaging have brought to the way we diagnose, monitor, and treat patients. In a way, simple medical imaging technologies, such as x-rays and ultrasounds, must have been as exciting for our medical predecessors as nuclear imaging is for us today. 

There are certain diseases in which medical imaging is more important than others, such as medullary thyroid carcinoma (MTC). In this article, we will explore where we stand with regard to nuclear imaging in MTC. 

A Longtime Target of Interest

“The cholecystokinin-2 receptor (CCK2R) has been a target of interest for molecular imaging and targeted radionuclide therapy for two decades,” Von Guggenberg et al wrote. The reason for this is that CCK2R is highly expressed in various tumors, including MTC. 

Continue Reading

Read more about MTC etiology 

In response to this, scientists have spent years developing radiolabeled CCK2R targeting peptide analogs. The development of them has an interesting history, and we have a long list of scientists to thank for their work. In 1998, Thomas Bear undertook the first scintigraphic visualization of tumor lesions in a patient who had metastasized MTC using I-label gastrin. In the same team, Martin Béhé successfully developed the first 111In-labeled gastrin derivatives that had a selective affinity for CCK2R. “Soon thereafter, additional research groups across Europe directed their attention to the preclinical development of peptide-based CCK2R targeting probes,” reported Von Guggenberg et al. 

Klinger et al explained why medical researchers are keen to devote so much time and energy to develop this branch of nuclear imaging. “The development of CCK2R targeting radiopeptides was driven mainly by the need to improve the medical care of MTC patients. The clinical management of thyroid cancer is of particularly high historical significance for nuclear medicine,” they wrote. “Already more than 70 years ago nuclear medicine images were acquired in patients suffering from thyroid disorders. Since then, molecular imaging has played an important role in diagnosing and managing thyroid cancer.” 

The crux of the cause: an increased ability to diagnose and manage thyroid cancer effectively. 

However, the stark reality is that CCK2R targeting probes are still not where we want them to be. Von Guggenberg and colleagues explained, “The preclinical development and search for optimal CCK2R targeting probes is still ongoing. A major issue remains metabolic stability, possibly affecting the tumor uptake and retention. Therefore, various attempts for further optimization of the peptide sequence are pursued currently.” 

Klinger et al wrote about similar concerns about CCK2R targeting: “The main limitation of the CCK2R targeting peptide analogs currently investigated in clinical trials remains their high sensitivity toward enzymatic degradation in vivo.” The answer? “By increasing the in vivo stability and bioavailability of the radiopeptide through co-administration of enzyme inhibitors, a highly improved targeting profile can be achieved.”

Improving the Targeting Profile

We will provide a brief summary of the attempts by medical researchers to do just that. One method that has already been mentioned uses enzyme inhibitors to prevent radiopeptides from metabolic degradation and hence increases their availability to bind to specific receptors. In a study using mice models, mice were co-injected with various radiolabeled minigastrin (MG) analogs and the neutral endopeptidase inhibitor phsophoramidon (PA). The results demonstrated increased in-vivo metabolic stability, which in turn improved radiopeptide uptake in CCK2R-expressing tumor xenografts in the mice. 

Read more about MTC diagnosis 

On this subject, Von Guggenberg et al wrote, “Since co-injection of . . . PA had a significant effect on metabolic stability and consequently the tumor uptake of [111In]In-DOTA-MG11, several research groups have focused on site-specific stabilization of MG11 to circumvent its fast degradation by proteases.”

Co-injection of PA into severe combined immunodeficiency (SCID) mice resulted in the tumor uptake of  [111In]In-DOTA-MG11 to be increased by a factor of 8, while maintaining low levels of kidney retention. As a result, “the authors suggested that the concept of enzyme inhibition might be a rational alternative to costly and time-consuming development of compound libraries,” the authors of the study wrote. 

In addition to the strategy of improving metabolic stability, other strategies include improving tumor-specific uptake. Von Guggenberg and colleagues wrote, “Pharmacological inhibition of the mTORC1 pathway using the allosteric mTORC1 inhibitor RAD001 (Everolimus) increased the level of CCK2R in AR42J and A431-CCK2R cells and consequently increased the receptor-specific cell uptake.” The value of increasing receptor-specific cell uptake is that it improves the therapeutic response of peptide receptor radionuclide therapy while limiting the dose delivered to CCK2R-expressing targets. 

Further Research Ongoing  

The attempts to make CCK2R targeting more efficient as outlined in this article is but a snippet of the work being carried out. However, it is likely to continue to be the direction of future clinical trials and studies: improving metabolic stability and increasing tumor-specific uptake. 

“New MG analogs with improved metabolic stability and reduced kidney uptake promise to have a significant impact in the diagnosis and therapy of CCK2R related malignancies,” Von Guggenberg et al concluded. ”Further preclinical development and clinical evidence will be reported in the near future to support these initial achievements.”


Von Guggenberg E, Kolenc P, Rottenburger C, Mikołajczak R, Hubalewska-Dydejczyk A. Update on preclinical development and clinical translation of cholecystokinin-2 receptor targeting radiopharmaceuticalsCancers. Published online November 18, 2021. doi:10.3390/cancers13225776

Klingler M, Hörmann AA, Guggenberg EV. Cholecystokinin-2 receptor targeting with radiolabeled peptides: current status and future directions. Curr Med Chem. 2020;27(41):7112-7132. doi:10.2174/0929867327666200625143035