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

Autor: Melpomeni Fani, Svetlana N. Rylova, Keelara Abiraj, C. Stoykow, Maria Luisa Tamma, Luigi Del Pozzo, Yvonne Kiefer, Helmut R. Maecke
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Physiology
Peptide Hormones
lcsh:Medicine
Pharmacology
Acetates
Biochemistry
030218 nuclear medicine & medical imaging
Diagnostic Radiology
Mice
0302 clinical medicine
Neoplasms
Medicine and Health Sciences
Somatostatin receptor 2
Tissue Distribution
Receptors
Somatostatin
Internalization
lcsh:Science
Tomography
media_common
Multidisciplinary
Radiochemistry
Molecular Structure
Chemistry
Radiology and Imaging
Physics
Animal Models
Molecular Imaging
Body Fluids
Somatostatin
Blood
Radioactivity
Liver
Experimental Organism Systems
030220 oncology & carcinogenesis
Physical Sciences
Heterografts
Anatomy
Research Article
Agonist
Biodistribution
medicine.drug_class
Imaging Techniques
media_common.quotation_subject
Neuroimaging
Mouse Models
Research and Analysis Methods
03 medical and health sciences
Heterocyclic Compounds
1-Ring
Model Organisms
Pharmacokinetics
In vivo
Diagnostic Medicine
medicine
Animals
Humans
Nuclear Physics
lcsh:R
Antagonist
Biology and Life Sciences
Kidneys
Renal System
Hormones
Disease Models
Animal
HEK293 Cells
Copper Radioisotopes
Positron-Emission Tomography
lcsh:Q
Radiopharmaceuticals
Positron Emission Tomography
Neuroscience
Zdroj: PLoS ONE, Vol 13, Iss 4, p e0195802 (2018)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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