Tamer M. Sakr

Labeling of ceftriaxone for infective inflammation imaging using 99mTc eluted from 99Mo/99mTc generator based on zirconium molybdate

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.

Biodistribution of 99mTc‐sunitinib as a potential radiotracer for tumor hypoxia imaging

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.

99mTc-amitrole as a novel selective imaging probe for solid tumor: In silico and preclinical pharmacological study

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.

Synthesis and preliminary affinity testing of 123I/125I-N-(3-iodophenyl)-2-methylpyrimidine-4,6-diamine as a novel potential lung scintigraphic agent

Radioiodinated N-(3-iodophenyl)-2-methylpyrimidine-4,6-diamine (radioiodinated IPMPD), a potential lung scintigraphic agent, was synthesized via direct electrophilic substitution. Factors affecting the radiochemical yield were studied in detail. High radiochemical yield (92.3 ± 2.3%) was reached. The compound is stable in vitro for 24 h. Radioiodinated IPMPD was biologically evaluated in normal Albino mice. The compound demonstrated high lung uptake (21.4 ± 1.7% of injected dose per gram organ at 15 min) and thus shows promise for lung perfusion scintigraphy.

Radioiodinated acebutolol as a new highly selective radiotracer for myocardial perfusion imaging

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.

Nano-technology contributions towards the development of high performance radioisotope generators: The future promise to meet the continuing clinical demand

Nanostructured materials attracted considerable attention because of its high surface area to volume ratio resulting from their nano-scale dimensions. This class of sorbents is expected to have a potential impact on enhancement the efficacy of radioisotope generators for diagnostic and therapeutic applications in nuclear medicine. This review provides a summary on the importance of nanostructured materials as effective sorbents for the development of clinical-scale radioisotope generators and outlining the assessment of recent developments, key challenges and promising access to the near future.

In Silico-Based Repositioning of Phosphinothricin as a Novel Technetium-99m Imaging Probe with Potential Anti-Cancer Activity

l-Phosphinothricin (glufosinate or 2-amino-4-((hydroxy(methyl) phosphinyl) butyric acid ammonium salt (AHPB)), which is a structural analog of glutamate, is a recognized herbicide that acts on weeds through inhibition of glutamine synthetase. Due to the structural similarity between phosphinothricin and some bisphosphonates (BPs), this study focuses on investigating the possibility of repurposing phosphinothricin as a bisphosphonate analogue, particularly in two medicine-related activities: image probing and as an anti-cancer drug. As BP is a competitive inhibitor of human farnesyl pyrophosphate synthase (HFPPS), in silico molecular docking and dynamic simulations studies were established to evaluate the binding and stability of phosphinothricin with HFPPS, while the results showed good binding and stability in the active site of the enzyme in relation to alendronate. For the purpose of inspecting bone-tissue accumulation of phosphinothricin, a technetium (99mTc)–phosphinothricin complex was developed and its stability and tissue distribution were scrutinized. The radioactive complex showed rapid, high and sustained uptake into bone tissues. Finally, the cytotoxic activity of phosphinothricin was tested against breast and lung cancer cells, with the results indicating cytotoxic activity in relation to alendronate. All the above results provide support for the use of phosphinothricin as a potential anti-cancer drug and of its technetium complex as an imaging probe.

Molecular modeling and preclinical evaluation of radioiodinated tenoxicam for inflammatory disease diagnosis

The aim of the presented study is to investigate a new promising radiopharmaceutical tracer able to visualize and differentiate inflammation versus infection in early stages. Radioiodinated tenoxicam (125I-tenoxicam) was prepared and its radiochemical yield and in vitro stability were assayed. The biodistribution studies were conducted on two different mice models: sterile inflammation and bacterial infection mice models. 125I-tenoxicam showed high T/NT accumulation in the inflammatory tissues revealing high selectivity to the inflammatory tissues in contrast to infection bearing mice. The docking study using CDOCKER protocol for tenoxicam and radioiodinated tenoxicam with COX enzymes was performed to confirm that radioiodinated tenoxicam still retaining COX enzymes selectivity.Graphical Abstract

I-131 doping of silver nanoparticles platform for tumor theranosis guided drug delivery

&NA; Nanotechnology may be applied in medicine where the utilization of nanoparticles (≤100 nm) for the delivery and targeting of theranostic agents is at the forefront of projects in cancer nano‐science. This study points a novel one step synthesis approach to build up polyethylene glycol capped silver nanoparticles doped with I‐131 radionuclide (131I‐doped Ag‐PEG NPs). The formula was prepared with average hydrodynamic size 21 nm, zeta potential – 25 mV, radiolabeling yield 98 ± 0.76%, and showed good in‐vitro stability in saline and mice serum. The in‐vitro cytotoxicity study of cold Ag‐PEG NPs formula as a drug carrier vehicle showed no cytotoxic effect on normal cells (WI‐38 cells) at a concentration below 3 &mgr;L/104 cells. The in‐vivo biodistribution pattern of 131I‐doped Ag‐PEG NPs in solid tumor bearing mice showed high radioactivity accumulation in tumor tissues with maximum uptake of 35.43 ± 1.12 and 63.8 ± 1.3% ID/g at 60 and 15 min post intravenous (I.V.) and intratumoral injection (I.T.), respectively. Great potential of T/NT ratios were obtained throughout the experimental time points with maximum ratios 45.23 ± 0.65 and 92.46 ± 1.02 at 60 and 15 min post I.V. and I.T. injection, respectively. Thus, 131I‐doped Ag‐PEG NPs formulation could be displayed as a great potential tumor nano‐sized theranostic probe. Graphical abstract Figure. No caption available.

Radioiodinated esmolol as a highly selective radiotracer for myocardial perfusion imaging: In silico study and preclinical evaluation

Challenges facing cardiovascular imaging necessitate innovation of better radiopharmaceuticals to augment or replace the existing ones. This research assesses the ability and competency of radioiodinated esmolol as a potential cardio selective imaging agent. Radioiodinated esmolol was synthesized with 97.3 ± 0.3% radiochemical yield and with high stability up to 48 h at room temperature as well as in rat serum. Molecular modeling study was performed to confirm the binding of iodinated esmolol to β1-adrenergic receptor. Its biodistribution studies in normal Swiss albino mice showed high heart uptake (38.5 ± 0.11%ID/g at 5 min p.i.), heart/liver ratio nearly 3.85:1 and heart/lungs ratio was about 7:1 at 5 min p.i. The evidenced selectivity of the radioiodinated esmolol to β1-adrenoceptor was confirmed by prior injection of cold esmolol. Gamma camera biodistribution pattern showed that radioiodinated esmolol accumulated selectively in heart.