ABSTRACT
Lactoperoxidase (LPO) inhibitors are very selective for solid tumor due to their high binding affinity to the LPO enzyme. A computational study was used to select top-ranked LPO inhibitor (alone and in complex with (99m)Tc) with high in silico affinity. The novel prepared (99m)Tc-amitrole complex demonstrated both in silico and in vivo high affinity toward solid tumors.(99m)Tc-amitrole was radio-synthesized with a high radiochemical yield (89.7±3.25). It showed in vitro stability for up to 6h. Its preclinical evaluation in solid tumor-bearing mice showed high retention and biological accumulation in solid tumor cells with a high Target/Non-Target (T/NT) ratio equal to 4.9 at 60min post-injection. The data described previously could recommend (99m)Tc-amitrole as potential targeting scintigraphic probe for solid tumor imaging.
Subject(s)
Amitrole/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Carcinoma, Ehrlich Tumor/diagnostic imaging , Computer-Aided Design , Drug Design , Enzyme Inhibitors/pharmacokinetics , Lactoperoxidase/antagonists & inhibitors , Radiopharmaceuticals/pharmacokinetics , Technetium/pharmacokinetics , Amitrole/administration & dosage , Amitrole/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/enzymology , Drug Stability , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Female , Hydrogen-Ion Concentration , Lactoperoxidase/metabolism , Mice , Molecular Docking Simulation , Molecular Structure , Radionuclide Imaging , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/chemistry , Structure-Activity Relationship , Technetium/administration & dosage , Technetium/chemistry , Tissue DistributionABSTRACT
Acebutolol was successfully labeled with (125) I via direct electrophilic substitution reaction. Radioiodinated acebutolol was prepared with a maximum radiochemical yield of 96.5 ± 0.3% and in vitro stability up to 72 h. The in vivo biological distribution of radioiodinated acebutolol showed high heart uptake of 37.8 ± 0.14% injected activity/g organ with low lungs and liver uptakes at 5 min post-injection. In vivo receptor blocking study was carried out in mice to evaluate its selectivity to heart. Radioiodinated acebutolol showed fast heart accumulation with high heart/liver ratio, which provides the ability for fast myocardial imaging with significant decrease in the radiation hazards risk on patients. So, radioiodinated acebutolol could be displayed as a radiotracer drug of choice in case of emergency patients for myocardial perfusion imaging.
Subject(s)
Acebutolol/pharmacokinetics , Myocardial Perfusion Imaging/methods , Radiopharmaceuticals/pharmacokinetics , Acebutolol/chemical synthesis , Animals , Iodine Radioisotopes/chemistry , Iodine Radioisotopes/pharmacokinetics , Male , Mice , Radiopharmaceuticals/chemical synthesis , Tissue DistributionABSTRACT
Tyrosine kinases are groups of enzymes, which are over-expressed in solid tumor cells, representing good targets for different drugs such as sunitinib (N-[2-(diethylamino)ethyl]-5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxamide). The aim of this work was to design and synthesize (99m)Tc-sunitinib radiotracer and to study its tumor binding specificity as a novel selective radiopharmaceutical for tumor hypoxia imaging. The in vivo biodistribution of (99m)Tc-sunitinib in tumor bearing mice showed high target/non-target (T/NT) ratio (T/NT ~ 3 at 60 min post injection). This preclinical high biological accumulation in tumor cells suggests that (99m)Tc-sunitinib is ready to go through the clinical trials as a potential selective radiotracer able to image tumor hypoxia.
Subject(s)
Indoles/pharmacokinetics , Neoplasms, Experimental/diagnostic imaging , Organotechnetium Compounds/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Animals , Cell Hypoxia , Indoles/chemical synthesis , Indoles/chemistry , Isotope Labeling , Mice , Organotechnetium Compounds/chemical synthesis , Pyrroles/chemistry , Radiopharmaceuticals/chemical synthesis , Sunitinib , Tomography, Emission-Computed, Single-PhotonABSTRACT
Zirconium molybdate gel was prepared by mixing (99)Mo, produced from (98)Mo(n,gamma) reaction and Zr solutions in nitrate media with excess H(2)O(2), and used as the base material for (99)Mo/(99m)Tc generator. The prepared generator showed a good performance. (99m)Tc eluted from the prepared generator passed the quality control tests with specifications meeting the requirements of European and US Pharmacopeias. The (99m)Tc eluate was used for labeling of cephalosporin analogue, ceftriaxone, which was then assessed for infection imaging in a mouse model. (99m)Tc-ceftriaxone was prepared at pH 9 with a radiochemical yield of 95+/-2% by adding (99m)Tc to 30 mg ceftriaxone in the presence of 50 microg SnCl(2).2H(2)O. Biodistribution studies in mice were carried out using experimentally induced infection in the left thigh using E. coli. Both thighs of the mice were dissected and counted to evaluate the ratio of bacterial infected thigh/contralateral thigh. (99m)Tc-ceftriaxone showed high uptake in the infectious lesion (T/NT =5.6+/-0.6 at 4h post injection). The abscess to normal muscle ratio indicated that (99m)Tc-ceftriaxone could be used for infection imaging. Besides, in vitro studies showed that (99m)Tc-ceftriaxone can differentiate between bacterial infection and sterile inflammation.