The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model

Abstract

Copper-64 is an attractive radionuclide for PET imaging and is frequently used in clinical applications. The aim of this study was to perform a side-by-side comparison of the in vitro and in vivo performance of 64Cu-NODAGA-JR11 (NODAGA = 1,4,7-triazacyclononane,1-glutaric acid,4,7-acetic acid, JR11 = p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(cbm)-Lys-Thr-Cys)D-Tyr-NH2), a somatostatin receptor 2 antagonist, with the clinically used sst2 agonist 64Cu-DOTA-TATE ((TATE = D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr). In vitro studies demonstrated Kd values of 5.7±0.95 nM (Bmax = 4.1±0.18 nM) for the antagonist 64/natCu-NODAGA-JR11 and 20.1±4.4. nM (Bmax = 0.48±0.18 nM) for the agonist 64/natCu-DOTA-TATE. Cell uptake studies showed the expected differences between agonists and antagonists. Whereas 64Cu-DOTA-TATE (the agonist) showed very effective internalization in the cell culture assay (with 50% internalized at 4 hours post-peptide addition under the given experimental conditions), 64Cu-NODAGA-JR11 (the antagonist) showed little internalization but strong receptor-mediated uptake at the cell membrane. Biodistribution studies of 64Cu-NODAGA-JR11 showed rapid blood clearance and tumor uptake with increasing tumor-to-relevant organ ratios within the first 4 hours and in some cases, 24 hours, respectively. The tumor washout was slow or non-existent in the first 4 hours, whereas the kidney washout was very efficient, leading to high and increasing tumor-to-kidney ratios over time. Specificity of tumor uptake was proven by co-injection of high excess of non-radiolabeled peptide, which led to >80% tumor blocking. 64Cu-DOTA-TATE showed less favorable pharmacokinetics, with the exception of lower kidney uptake. Blood clearance was distinctly slower and persistent higher blood values were found at 24 hours. Uptake in the liver and lung was relatively high and also persistent. The tumor uptake was specific and similar to that of 64Cu-NODAGA-JR11 at 1 h, but release from the tumor was very fast, particularly between 4 and 24 hours. Tumor-to-normal organ ratios were distinctly lower after 1 hour. This is indicative of insufficient in vivo stability. PET studies of 64Cu-NODAGA-JR11 reflected the biodistribution data with nicely delineated tumor and low background. 64Cu-NODAGA-JR11 shows promising pharmacokinetic properties for further translation into the clinic.

Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: 64Cu- and 225Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models

“…4) is most probably due to free radionuclides, because macrocyclic copperchelates can suffer from limited in vivo stability against superoxide dismutase in the liver (21). Rylova et al reported that 64 Cu-DOTA-TATE is more stable in humans than in mice (22). It is possible that 64 Cu-or 225 Ac-labeled FAPI-04 shows a different biodistribution in humans, especially for liver uptake.…”

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

“…The hypothesis of a ligand rebinding mechanism has been put forward, but this still requires some investigation before it can be validated. These first results were confirmed by preclinical studies and by preliminary clinical trials and seems to show superior results for antagonist-based tracers than agonists [ 218 , 219 , 220 , 221 ]. The first comparative study of antagonists with Octreoscan ® confirmed the good characteristics of the [ 111 In]-DOTA-BASS analog, and better accumulation at the level of the tumor and better visualization of metastases.…”

In Vivo Imaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET

“…The earliest time point for quantitative imaging after injection of labelled abatacept in mice is thus 24 h. We chose 48 h to guarantee equilibrated distribution and as 48 h provided better imaging results than 18 h in our former study with the related protein 111 In-DOTA-belatacept [20,21]. For labelling, we chose Cu-64 as it provides high spatial resolution due to its low decay energy (0.7 mm mean range in water before annihilation) and as 64 Cu-NODAGA complexes have an excellent stability in vivo [36][37][38]. The physical (radioactivity decay) half-life of 12.7 h resulted in signal loss of 9 90 % within the 48 h between tracer injection and imaging.…”