CCKB

A newly developed PET imaging agent has been found to be effective in identifying medullary thyroid cancer (MTC) in preclinical and clinical studies. The results of the studies indicate that the PET imaging agent may be a promising theranostic candidate for clinical use. 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. 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 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.

Depression is one of the most common mental illnesses in the world, but current anti-depressants have yet to meet the needs of many patients. Neuroscientists recently discovered a small molecule that can effectively alleviate stress-induced depressive symptoms in mice by preventing aversive memory formation with a lower dosage, offering a new direction for developing anti-depressants in the future. Depression is one of the most common mental illnesses in the world, but current anti-depressants have yet to meet the needs of many patients. Neuroscientists from City University of Hong Kong (CityU) recently discovered a small molecule that can effectively alleviate stress-induced depressive symptoms in mice by preventing aversive memory formation with a lower dosage, offering a new direction for developing anti-depressants in the future. "Depression affects millions of individuals worldwide, necessitating more effective treatments. Conventional methods, such as drug therapy with delayed onset of action and psychotherapy, have limitations in yielding satisfactory results for many patients. A pioneering advancement in treatment is urgently needed," said Professor He Jufang, Wong Chun Hong Chair Professor in Translational Neuroscience at CityU. Previous research found that stress leads to neural plasticity changes in brain's valence-coding systems ("valence" refers to the degree to which something is pleasurable or aversive), which are strongly associated with depression, post-traumatic stress disorders and anxiety disorders. Also, some studies revealed that depression is correlated with the hyperactivated amygdala. "However, the neural mechanism that mediates depression in amygdala is still poorly understood," said Professor He. Over the years, Professor He's research group has focused on memory formation and encoding studies. Previously, they discovered that cholecystokinin (CCK), a key neuromodulator, is crucial for inducing long-term potentiation (LTP) -- a lasting increase in communication strength between neurons -- to enable memory formation. They also found that the CCK and CCK-B receptors (CCKBR is one of three known types of CCK receptors in the central nervous system) mediate neuroplasticity, as well as visual and sound associative memory formation, in the auditory cortex, and trace fear memory formation in the amygdala. Other studies have found that CCKBR antagonist (which blocks the binding of the CCK and CCK-B receptors, thus inhibiting the effect of the binding) exhibited an anti-depressant effect in mice. So Professor He's group hypothesized that CCK might facilitate aversive memory formation by enabling LTP in the basolateral amygdala (BLA) -- a brain region involved in processing emotional memories and thought to be dysregulated in depression, thus enhancing the development of depression. In their latest study, they tested this hypothesis using various experimental methods, including in vitro electrophysiological recording, optogenetic manipulation, drug manipulation and behavioural analysis of mice, to examine the critical role of CCK and CCKBR in depression. They found that a CCKBR antagonist called YM022 had an anti-depressant-like effect by blocking neuroplasticity-caused aversive memory formation in mice. The results of the in-vitro recording in the BLA showed that the YM022 significantly suppressed neuroplasticity. The neuroplasticity induction rate reached 72.3% in the control group; but it was only 10.2% in the drug-treated group. Moreover, the team underwent a series of behavioural tests to determine the antagonist's efficacy. The results showed that depressive behaviours in mice treated with a CCKBR antagonist was reduced. "Remarkably, the YM022 shows anxiolytic effects with a dose of 3.0 ug/kg, which is 3,000 times lower than the required dosage of current antidepressants," said Professor He. "These results indicate that CCKBR is a potential target for depression treatment, and that the selected antagonist, YM022, may be a good anti-depressant candidate due to its extremely small effective dose. This paves the way for targeted drug development that specifically addresses the abnormalities observed in the basolateral amygdala." Next, the research team will focus on the precise mechanisms and potential side effects of CCKBR antagonists to set the stage for future clinical trials involving human subjects. The research was supported by Hong Kong Research Grants Council, the Innovation and Technology Fund, the Health and Medical Research Fund, and the following charitable foundations: the Wong Chun Hong Endowed Chair Professorship, the Charlie Lee Charitable Foundation, and the Fong Shu Fook Tong Foundation.