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The folate receptor has attracted much attention in the field of radiolabeled imaging agents due to the significant difference in its expression levels between tumor cells and most normal cells. However, the development of folate-based imaging agents has been limited by their high uptake in the kidney. In this study, to reduce the high renal uptake of radiolabeled folate-based tracers, a phenyl-isonitrile folate derivative (CNMBFA) was designed and labeled with technetium-99m. The complex obtained via the one-step kit labeling method had a high labeling yield (>95%) and high in vitro stability and hydrophilicity (log D 7.4 = -1.72 ± 0.13). The results of the in vitro cell uptake and blocking studies and competitive binding experiments revealed that the [[ 99m Tc]Tc-(CNMBFA) 6 ] + complex was specific for the folate receptor. Biodistribution and inhibition studies in KB tumor-bearing mice revealed moderate uptake and significant inhibition of the complex in tumors, whereas the renal uptake of [[ 99m Tc]Tc-(CNMBFA) 6 ] + was significantly lower than that of previously reported tracers. Micro-SPECT/CT images further supported its ability to target the folate receptor for tumor imaging. Taken together, these results indicate that [[ 99m Tc]Tc-(CNMBFA) 6 ] + is a potential tumor imaging agent that has good tumor-targeting properties with minimal radiation damage to the kidney.

The aim of the presented work was to develop folate based radiolabeled compound intended to be used as diagnostic aid for the various folate-receptor overexpressing cancers eg. breast cancer, brain tumors, lung cancer etc. Folate was directly radiolabeled with Tc-99m using Quality-by-Design and encapsulated in micellar nanocarriers. The authors are of the view that the stable radiolabeled folate could be of potential diagnostic value in cancers overexpressing folate receptors thereby opening novel possibilities to diagnostic applications of radiolabeled folate. SUMMARY FOR TECHNICAL NOTES: Folic acid was directly radiolabeled with Tc-99m utilizing a quality by design approach. The experimental trials were designed using the Box-Behenken design with the concentration of drug, concentration of reducing agent and the incubation time as dependent variable and percent radiolabeling as the response for the same. The applied design in the method section was validated with a series of experiments and the percent labeling of the FA with Tc-99m was found to be around 94%. The radiolabeled compound was imperilled to stability evaluation by incubating the same with serum and physiological pH and the same was found to be stable at the end of 4h. On subjecting to DTPA challenge test, the compound displayed no change in the radiolabeling percentage thereby indicating the robustness of the formed Tc-99m-FA complex, The radiolabeled Tc-99m-FA was further encapsulated into micellar nanocarriers and the same were also found to be robust and stable., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of individuals globally. It is characterized by the loss of dopaminergic neurons in Substantia Nigra pars compacta (SNc) and striatum. Neuroimaging techniques such as single-photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI) help diagnosing PD. In this study, the focus was on developing technetium-99 m ([ 99m Tc]Tc) radiolabeled drug delivery systems using plant-derived compounds for the diagnosis of PD. Madecassoside (MA), a plant-derived compound, was conjugated with Levodopa (L-DOPA) to form MA-L-DOPA, which was then encapsulated using Poly Lactic-co-Glycolic Acid (PLGA) to create MA-PLGA and MA-L-DOPA-PLGA nanocapsules. Extensive structural analysis was performed using various methods such as Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), liquid chromatography-mass spectrometry (LC-MS), thin layer chromatography (TLC), high performance liquid chromatography (HPLC), dynamic light scattering (DLS), and scanning electron microscopy (SEM) to characterize the synthesized products. Radiochemical yields of radiolabeled compounds were determined using thin layer radio chromatography (TLRC) and high performance liquid radio chromatography (HPLRC) methods. In vitro cell culture studies were conducted on human neuroblastoma (SH-SY5Y) and rat pheochromocytoma (PC-12) cell lines to assess the incorporation of [ 99m Tc]Tc radiolabeled compounds ([ 99m Tc]Tc-MA, [ 99m Tc]Tc-MA-L-DOPA, [ 99m Tc]Tc-MA-PLGA and [ 99m Tc]Tc-MA-L-DOPA-PLGA) and the cytotoxicity of inactive compounds (MA and MA-L-DOPA compounds and encapsulated compounds (MA-PLGA and MA-L-DOPA-PLGA). Additionally, the biodistribution studies were carried out on healthy male Sprague-Dawley rats and a Parkinson's disease experimental model to evaluate the compounds' bioactivity using the radiolabeled compounds. The radiochemical yields of all radiolabeled compounds except [ 99m Tc]Tc-L-DOPA-PLGA were above 95% and had stability over 6 h. The cytotoxic effects of all substances on SH-SY5Y and PC-12 cells increase with increasing concentration values. The uptake values of PLGA-encapsulated compounds are statistically significant in SH-SY5Y and PC-12 cells. The biodistribution studies showed that [99mTc]Tc-MA is predominantly retained in specific organs and brain regions, with notable uptake in the prostate, muscle, and midbrain. PLGA-encapsulation led to higher uptake in certain organs, suggesting its biodegradable nature may enhance tissue retention, and surface modifications might further optimize brain penetration. Overall, the results indicate that radiolabeled plant-derived encapsulated drug delivery systems with [ 99m Tc]Tc hold potential as diagnostic agents for PD symptoms. This study contributes to the advancement of drug delivery agents in the field of brain research., (© 2024. The Author(s).)

The specific expression of prostate-specific membrane antigen (PSMA) makes it an ideal target for the diagnosis and treatment of prostate cancer. Currently, many 99m Tc-labeled PSMA-targeted tracers have been developed. However, the high renal uptake of these 99m Tc-labeled tracers is a common problem that limits their clinical application. In this work, the ligand (EUKPG) using D Pro-Gly as the linker was synthesized and three 99m Tc-labeled complexes ([ 99m Tc]Tc-EUKPG-EDDA, [ 99m Tc]Tc-EUKPG-TPPTS, [ 99m Tc]Tc-EUKPG-TPPMS) with different coligands were prepared and evaluated. Among them, [ 99m Tc]Tc-EUKPG-EDDA showed the most favorable pharmacokinetic properties, with significantly reduced uptake in the kidney (14.04 ± 0.23% ID/g), rapid clearance and low uptake in nontarget organs, thus making it to exhibit high tumor-to-background ratios (tumor/blood: 7.47, tumor/muscle: 12.65). Affinity studies have shown that it has high specificity for PSMA both in vivo and in vitro . Therefore, [ 99m Tc]Tc-EUKPG-EDDA has great potential as a promising molecular tracer to target PSMA for tumor imaging.

Objective: Prostate-specific membrane antigen (PSMA) is a well-known biomarker of prostate cancer. Previously, our group reported that the succinimidyl-cystatin-urea-glutamate (SCUE) moiety has a high affinity for PSMA. In this study, we developed the novel technetium-99m-labeled PSMA-targeting probe "[ 99m Tc]Tc-(Ham-SCUE) 2 " based on a hydroxamamide chelate with a bivalent SCUE and evaluated its potential as a SPECT imaging probe for the diagnosis of PSMA-expressing prostate cancer., Methods: Ham-SCUE was synthesized by a one-step reaction with Ham-Mal and cysteine-urea-glutamine. Then, Ham-SCUE was reacted with [ 99m Tc]NaTcO 4 for 10 min at room temperature to obtain [ 99m Tc]Tc-(Ham-SCUE) 2 . [ 99m Tc]Tc-(Ham-SCUE) 2 was added to LNCaP (high PSMA expression) cells or PC3 (low PSMA expression) cells, and their radioactivity was measured 60 min after administration. The blocking study was performed by co-incubation of LNCaP cells with various concentrations of 2-PMPA (a PSMA inhibitor) for 15 min before adding [ 99m Tc]Tc-(Ham-SCUE) 2 . The biodistribution of [ 99m Tc]Tc-(Ham-SCUE) 2 in LNCaP/PC3 dual xenografted C.B.-17/Icr scid/scid Jcl mice was evaluated for 120 min after intravenous injection. The blocking study was performed by pretreatment of mice with 2-PMPA (10 mg/kg weight)., Results: [ 99m Tc]Tc-(Ham-SCUE) 2 was acquired at radiochemical yields of 56% with a radiochemical purity of over 95%. The cellular uptake level of [ 99m Tc]Tc-(Ham-SCUE) 2 by LNCaP cells was significantly higher than that by PC3 cells (LNCaP: 11.12 ± 0.71 vs. PC3: 1.40 ± 0.13%uptake/mg protein, p < 0.01), and the uptake was significantly suppressed by pretreatment with 2-PMPA (2.56 ± 0.37%uptake/mg protein, p < 0.05). IC 50 of 2-PMPA was 245 ± 47 nM. In the in vivo study, the radioactivity of LNCaP tumor tissue was significantly higher than that of PC3 tumor tissue at 120 min after the administration of [ 99m Tc]Tc-(Ham-SCUE) 2 (LNCaP: 9.97 ± 2.79, PC3: 1.16 ± 0.23%ID/g, p < 0.01), and was suppressed by pretreatment with 2-PMPA (2.50 ± 0.45%ID/g, p < 0.01)., Conclusion: [ 99m Tc]Tc-(Ham-SCUE) 2 has the potential to be a SPECT imaging agent for diagnosing high PSMA-expressing prostate cancer., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

We report the synthesis, characterization, and in vitro biological activities of [Re(η 6 -arene) 2 ] + -terpyridine conjugates and their Cu II complexes. The terpyridine (terpy) chelators were attached to the [Re(η 6 -arene) 2 ] + scaffold via secondary amine linkers allowing for heteroleptic mono- and homoleptic bis-terpyridine-substituted chelators. Complexation with CuCl 2 afforded the respective square pyramidal [Cu(terpy)Cl 2 ] complexes hosted on the [Re(η 6 -arene) 2 ] + scaffold. The chelator conjugates and their respective complexes were found to be remarkably cytotoxic against malignant HT29 and A549 human cancer cell lines in vitro with IC 50 values in the low micromolar range. Mitochondrial respiration disruption was identified as a possible mode of action of these novel drug candidates. Crucially, the [Re(η 6 -arene) 2 ] + hosts delivered water solubility of the otherwise insoluble [Cu(terpy)Cl 2 ] motif. Importantly, the homoleptic [ 99m Tc(η 6 -arene) 2 ] + -terpyridine conjugate is available in a single step, which enables the presented system to be used as a theranostic approach to modern medicinal inorganic chemistry.

99m Tc is a well-known radionuclide that is widely used and readily available for SPECT/CT (Single-Photon Emission Computed Tomography) diagnosis. However, commercial isotope carriers are not specific enough to tumours, rapidly clear from the bloodstream, and are not safe. To overcome these limitations, we suggest immunologically compatible recombinant proteins containing a combination of metal binding sites as 99m Tc chelators and several different tumour-specific ligands for early detection of tumours. E1b protein containing metal-binding centres and tumour-specific ligands targeting integrin α v β 3 and nucleolin, as well as a short Cys-rich sequence, was artificially constructed. It was produced in E. coli , purified by metal-chelate chromatography, and used to obtain a complex with 99m Tc. This was administered intravenously to healthy Balb/C mice at an activity dose of about 80 MBq per mouse, and the biodistribution was studied by SPECT/CT for 24 h. Free sodium 99m Tc-pertechnetate at the same dose was used as a reference. The selectivity of 99m Tc-E1b and the kinetics of isotope retention in tumours were then investigated in experiments in C57Bl/6 and Balb/C mice with subcutaneously transplanted lung carcinoma (LLC) or mammary adenocarcinoma (Ca755, EMT6, or 4T1). The radionuclide distribution ratio in tumour and adjacent normal tissue (T/N) steadily increased over 24 h, reaching 15.7 ± 4.2 for EMT6, 16.5 ± 3.8 for Ca755, 6.7 ± 4.2 for LLC, and 7.5 ± 3.1 for 4T1.

18 F-2-fluoro-2-deoxy-d-glucose ([ 18 F]FDG) has been the most used positron emission tomography imaging agent for clinical applications. Single photon emission computed tomography (SPECT) imaging is cheaper and used more widely for diagnostic use, but there is no SPECT tumor imaging agent for clinical applications comparable to [ 18 F]FDG. Mannose is a C2 epimer of glucose and can also be transported into tumor cells via glucose transporters (GLUTs). To develop a novel SPECT tumor imaging agent with satisfactory tumor uptake and tumor/nontarget ratios, here a mannose derivative (CN7DM) was synthesized and radiolabeled with technetium-99m to prepare [ 99m Tc]Tc-CN7DM. The six-coordinated structure of [ 99m Tc]Tc-CN7DM was confirmed by the corresponding rhenium compound (Re-CN7DM). [ 99m Tc]Tc-CN7DM was transported into cancer cells via GLUTs and may be trapped in the cancer cells by electrostatic attraction. The probe exhibited high uptake in tumors and low uptake in nontarget tissues in mice bearing different tumors, indicating that [ 99m Tc]Tc-CN7DM exhibited promising potential for SPECT tumor imaging and warranted further clinical investigation.

Isosaccharinic acid (HISA, or ISA in its deprotonated form) is the main degradation product of cellulose under alkaline conditions. It can form strong complexes with radionuclides and other toxic metal ions, eventually enhancing their mobility in the context of nuclear waste repositories and other environmental systems. 99 Tc is a redox-sensitive, long-lived fission product produced in high yield in nuclear reactors. The solubility of 99 Tc(IV) was investigated in 0.5 M NaCl‒NaISA‒NaOH solutions with 6 ≤ pH m  ≤ 12.5 and 10 -6  M ≤ [ISA] ≤ 0.2 M. Complete chemical and thermodynamic models were derived on the basis of solubility data, (pe + pH m ) measurements, redox speciation, and solid phase characterization. These models include the previously unreported aqueous complexes TcO(OH)(ISA) 2 ‒ and TcO(OH) 2 (ISA) 2 2- . In spite of the small size and high polarizability of the Tc 4+ metal ion, the Tc(IV)-ISA complexes described in this work are significantly weaker than other ISA complexes formed with larger M 4+ metal ions, i.e., Zr, Pu and U. This unexpected behavior can be possibly explained by the strong hydrolysis of Tc(IV) and corresponding stabilization of the TcO 2+ moiety, which does not occur for other M(IV) systems. Thermodynamic data derived in this work can be implemented in geochemical calculations of relevance in the context of nuclear waste disposal and other environmental applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Antibiotic resistance is a burden on the healthcare system. In present study, we have labeled an antibiotic named Colistimethate sodium (CMS) with technetium-99m ( 99m Tc) to develop a SPECT based imaging tracer., Methods: We standardised the labeling using 0.5-2 mg of CMS (in water) using stannous chloride dihydrate as a reducing agent followed by addition of 370 ± 74 MBq of 99m Tc. A group of mice were injected intravenously (in tail vein) with 4-6 MBq of [ 99m Tc]Tc-CMS diluted with saline and euthanized at various time intervals. microSPECT Imaging (ϒ-eye) was acquired to study the biodistribution in the healthy mice., Results: We standardised the labeling using 0.5 mg of colistin in 0.5 ml of saline with addition of 30 μg stannous chloride dihydrate. The retention factor value was 0.1-0.3 as compared to 0.9-1.0 for free 99m Tc by TLC and retention time was found to be 14.2 ± 1.3 min as evaluated by HPLC. The biodistribution data showed uptake in lungs, spleen, and liver at 30 min but the uptake decreased in lung at 60 min. The imaging data corroborated with the biodistribution data., Conclusions: We could successfully label [ 99m Tc]Tc-CMS 99m Tc and we could study its biodistribution in healthy mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cardiovascular diseases, including fatal myocardial infarctions from atheromatous plaques, are the primary global mortality cause. Detecting stenotic atheromatous plaques is possible through coronary angiography, but vulnerable plaques with eccentric remodeling are undetectable with current diagnostic methods. Addressing this challenge, our group developed a radiopharmaceutical drug targeting vascular cell adhesion molecule 1 (VCAM-1), radiolabeled with technetium-99m. Given the absence of a monograph in the European Pharmacopoeia, and in order to draft the investigational medicinal product documentation, analytical methods had to be validated by high performance liquid chromatography (HPLC) and thin layer chromatography (TLC) to determine the radiochemical purity (RCP) of 99m Tc-cAbVCAM1-5. This study therefore presents the results of the validation of analytical methods obtained in this context. The method validation followed the European Association of Nuclear Medicine (EANM) recommendations adapted from ICH Q2(R1), ensuring conformity with specificity, accuracy, repeatability and intermediate precision, linearity, robustness, quantification limit (LoQ), and range criteria. Regarding the results of specificity, both HPLC and TLC methods demonstrated excellent separation of 99m Tc-cAbVCAM1-5 from impurities 99m TcO4 - . Accuracy results indicated recovery percentages within the range of 99.52-101.40% for the HPLC and 99.51-101.97% for TLC, ensuring reliable measurements for each concentration of 99m TcO 4 - . Precision of the methods was validated by assessing repeatability and intermediate precision. Linearity was determined over the usual concentrations range and the correlation coefficient was greater than 0.99 for both methods. The limit of quantification was measured by diluting the 99m TcO 4 - to obtain a signal-to-noise ratio of around 10:1. Under these conditions, we obtained an LOQ of 2.10 MBq/mL for HPLC and 2Mbq/mL for TLC. In conclusion, the analytical methods developed in this study comply with EANM recommendations. This therefore allows us to correctly assess the radiochemical purity of 99m Tc-cAbVCAM1-5, a new radiotracer targeting inflammation in vulnerable plaques., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inflammatory diseases including rheumatoid arthritis are major health problems. Although different techniques and drugs are clinically available for the diagnosis and therapy of the disease, novel approaches regarding radiolabeled drug delivery systems are researched. Hence, in the present study, it was aimed to design, prepare, and characterize 99m Tc-radiolabeled and tofacitinib citrate-encapsulated microsphere loaded poloxamer in situ gel formulations for the intra-articular treatment. Among nine different microsphere formulations, MS/TOFA-9 was chosen as the most proper one due to particle size, high encapsulation efficiency, and in vitro drug release behavior. Poloxamer 338 at a concentration of 15% was used to prepare in situ gel formulations. For intra-articular administration, microspheres were dispersed in an in situ gel containing 15% Poloxamer 338 and characterized in terms of gelation temperature, viscosity, rheological, mechanical, and spreadability properties. After the determination of the safe dose for MS/TOFA-9 and PLX-MS/TOFA-9 as 40 µL/mL in the cell culture study performed on healthy cells, the high anti-inflammatory effects were due to significant cellular inhibition of fibroblasts. In the radiolabeling studies with 99m Tc, the optimum radiolabeling condition was determined as 200 ppm SnCl 2 and 0.5 mg ascorbic acid, and both 99m Tc-MS/TOFA-9 and 99m Tc-PLX-MS/TOFA-9 exhibited high cellular binding capacity. In conclusion, although further in vivo experiments are required, PLX-MS/TOFA-9 was found to be a promising agent for intra-articular injection in rheumatoid arthritis., (© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)

A folic acid-targeted polyurea (PURE) dendrimer was easily radiolabelled with Technetium-99m ( 99m Tc-PURE G4 -FA 2 ) avoiding the use of additional ligands and bioconjugation chemistry. This straightforward strategy is enabled in PURE dendrimers due to their favourable surface terminal groups configuration, showing coordination capabilities and turning these biodendrimers into attractive platforms for nanoradiotheranostics.

Aim: Nano-hydroxyapatite (nHA) is a good nanocarrier to load 223 Ra, but the low specific activity (sp.act.) of 223 Ra@nHA limits its application in medicine. Methods: We proposed a method for preparing nHA using PEG as a template, which significantly increases the sp.act of 223 Ra@nHA and a new method to loaded 99m Tc for in vivo tracking. Results: The nHA synthesized using PEG as a template was associated with higher sp.act for 223 Ra in comparison to nHA with identical particle size and without PEG. The nHA load 99m Tc-MDP was associated with higher labeling rate and stability in comparison to 99m Tc. Conclusion: All these findings suggest that using PEG as a template and 99m Tc-MDP could be the most effective of synthetic 223 Ra/ 99m Tc@nHA.

Radiolabeling of bionanomaterials with technetium-99m ( 99m Tc) has become a promising approach in combining the benefits of nanotechnology and nuclear medicine for diagnostic and therapeutic purposes. This review is intended to provide a comprehensive overview of the state-of-the-art of radiolabeling of bionanomaterials with 99m Tc, highlighting the synthesis methods, labeling mechanisms, biological evaluation, physicochemical characterization and clinical applications of 99m Tc-labeled bionanomaterials. Various types of nanomaterials are considered in the review, including lipid- and protein-based nanosystems, dendrimers and polymeric nanomaterials. Moreover, the review assesses the challenges presented by this emerging field, such as stability of the radiolabel, potential toxicity of the nanomaterials and regulatory aspects. Finally, promising future perspectives and areas of research development in 99m Tc-labeled bionanomaterials are discussed.

Poly ADP-ribose polymerase (PARP) plays an important role in the DNA repair process and has become an attractive target for cancer therapy in recent years. Given that niraparib has good clinical efficacy as a PARP inhibitor, this study aimed to develop radiolabeled niraparib derivatives for tumor imaging to detect PARP expression and improve the accuracy of stratified patient therapy. The niraparib isonitrile derivative (CNPN) was designed, synthesized, and radiolabeled to obtain the [ 99m Tc]Tc-CNPN complex with high radiochemical purity (>95%). It was lipophilic and stable in vitro . In HeLa cell experiments, the uptake of [ 99m Tc]Tc-CNPN was effectively inhibited by the ligand CNPN, indicating the binding affinity for PARP. According to the biodistribution studies of HeLa tumor-bearing mice, [ 99m Tc]Tc-CNPN has moderate tumor uptake and can be effectively inhibited, demonstrating its specificity for targeting PARP. The SPECT imaging results showed that [ 99m Tc]Tc-CNPN had tumor uptake at 2 h postinjection. All of the results of this study indicated that [ 99m Tc]Tc-CNPN is a promising tumor imaging agent that targets PARP.

The aim of the work presented in this manuscript was to radiolabel methotrexate and prepare radiolabeled methotrexate micelles, an antifolate drug with Tc-99m using QbD approach. The radiolabeling was executed using the experimental design and the radiolabeled drug was further encapsulated in micelles. The authors are of the view that the radiolabeled MTX could be used to target the folate receptor overexpressing cancers such as the kidney, colorectal, breast, brain etc thereby opening newer possibilities to the theranostic applications of the formed conjugate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Benchtop 99 Mo/ 99m Tc and 188 W/ 188 Re generators enable economical production of molecular theranostic 99m Tc and 188 Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates 99m Tc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with 99m Tc and 188 Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with 99m Tc and 188 Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each 99m Tc/ 188 Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with 99m Tc and 188 Re using kit-based methods to furnish the isostructural compounds M-DP1-PSMAt and M-DP2-PSMAt (M = [ 99m Tc]Tc, [ 188 Re]Re). All 99m Tc/ 188 Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18-30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of 99m Tc/ 188 Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting 99m Tc/ 188 Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced 177 Lu radiopharmaceuticals or PET/CT infrastructure., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Despite enormous advancements in its management, cancer is the world's primary cause of mortality. Therefore, tremendous strides were made to produce intelligent theranostics with mitigated side effects and improved specificity and efficiency. Thus, we developed a pH-sensitive theranostic platform composed of dextran immobilized zinc oxide nanoparticles, loaded with doxorubicin and radiolabeled with the technetium-99m radionuclide ( 99m Tc-labelled DOX-loaded ZnO@dextran). The platform measured 11.5 nm in diameter with -12 mV zeta potential, 88% DOX loading efficiency and 98.5% radiolabeling efficiency. It showed DOX release in a pH-responsive manner, releasing 93.1% cumulatively at pH 5 but just 7% at pH 7.4. It showed improved intracellular uptake, which resulted in a high growth suppressive effect against MCF-7 cancer cells as compared to the free DOX. It boasted a 4 times lower IC 50 than DOX, indicating its significant anti-proliferative potential (0.14 and 0.55 μg ml -1 , respectively). The in vitro biological evaluation revealed that its molecular mode of anti-proliferative action included downregulating Cdk-2, which provoked G1/S cell cycle arrest, and upregulating both the intracellular ROS level and caspase-3, which induced apoptosis and necrosis. The in vivo experiments in Ehrlich-ascites carcinoma bearing mice demonstrated that DOX-loaded ZnO@dextran showed a considerable 4-fold increase in anti-tumor efficacy compared to DOX. Moreover, by utilizing the diagnostic radionuclide ( 99m Tc), the radiolabeled platform ( 99m Tc-labelled DOX-loaded ZnO@dextran) was in vivo monitored in tumor-bearing mice, revealing high tumor accumulation (14% ID g -1 at 1 h p.i.) and reduced uptake in non-target organs with a 17.5 T/NT ratio at 1 h p.i. Hence, 99m Tc-labelled DOX-loaded ZnO@dextran could be recommended as a rectified tumor-targeted theranostic platform.

Chlorambucil is an alkylating drug that finds application towards chemotherapy of different types of cancers. In order to explore the possibility of utilization of this drug as an imaging agent for early diagnosis of solid tumors, attempt was made to synthesize a 99m Tc complex of chlorambucil and evaluate its potential in tumor bearing small animal model. HYNIC-chlorambucil was synthesized by conjugation of HYNIC with chlorambucil via an ethylenediamine linker. All the intermediates and final product were purified and characterized by standard spectroscopic techniques viz. FT-IR, 1 H/ 13 C-NMR as well as by mass spectrometry. HYNIC-chlorambucil conjugate was radiolabeled with [ 99m Tc]Tc and found to be formed with > 95 % radiochemical purity via RP-HPLC studies. The partition coefficient (Log 10 P o/w ) of the synthesized complex was found to be -0.78 ± 0.25 which indicated the moderate hydrophilic nature for the complex. Biological behaviour of [ 99m Tc]Tc-HYNIC-chlorambucil, studied in fibrosarcoma bearing Swiss mice, revealed a tumor uptake of about 4.16 ± 1.52 %IA/g at 30 min post-administration, which declined to 1.91 ± 0.13 % IA/g and 1.42 ± 0.14 %IA/g at 1 h and 2 h post-administration, respectively. A comparison of different [ 99m Tc]Tc-chlorambucil derivatives (reported in the contemporary literature) formulated using different methodologies revealed that tumor uptake and pharmacokinetics exhibited by these agents strongly depend on the lipophilicity/hydrophilicity of such agents, which in turn is dependent on the bifunctional chelators used for formulating the radiolabeled chlorambucils., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sulfur quantum dots (SQDs) as free heavy metal element quantum dots have promising applications in diagnosis and therapy; however, SQDs' in vivo biodistribution has not been studied. In the current study, SQDs were synthesized directly from cheap sublimated sulfur powder via a one-pot solvothermal method, and sucrose was used as a stabilizer to enhance stability and biocompatibility. The as-obtained SQDs with an average size of 4.6 nm exhibited great water dispersity, highly favorable quantum yield (21.5%), and uniformly spherical shape which were confirmed by UV-Vis, fluorescence spectrophotometer, TEM, and FESEM/EDX/PSA analyses. Moreover, the as-synthesized SQDs had very low cytotoxicity based on cancer (C26) and normal (L929) cell lines via MTT assay. And also, SQDs were radio-labeled directly by Technetium-99m ( 99m Tc), which had good stability ranging from 86 to 99% in PBS and human serum. The SQDs' cell uptake on C26 and L929 cell lines demonstrated that cancer cells had more uptake than normal cells by increasing concentrations. Moreover, SQDs' in vivo biodistribution results displayed high kidney dose accumulation and rapid renal clearance, making them suitable for imaging and therapeutic applications., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study investigates the feasibility of estimating the radioactivity of radiopharmaceuticals using shielded syringes. The radioactivities of 99m Tc-MDP, 99m Tc-HMDP, 99m Tc-ECD, 99m Tc-MAG 3 , and 123 I-IMP were measured using a dose calibrator. Correlation coefficients and regression equations were obtained from the radioactivity in the shielded and unshielded syringes. 99m Tc-MDP was also measured for residual radioactivity after the administration. The correlation coefficients of 99m Tc-MDP, 99m Tc-HMDP, 99m Tc-ECD, 99m Tc-MAG 3 , and 123 I-IMP were r s  = 0.9998, r s  = 0.9997, r s  = 0.9999, r s  = 0.9998, and r s  = 0.9888, respectively. The regression equations were y = 0.0364x + 0.0913, y = 0.0349x + 0.0273, y = 0.0343x - 0.0018, y = 0.0522x + 0.1215, and y = 0.0383x + 0.0058, respectively. The correlation coefficient for the residual radioactivity of 99m Tc-MDP was r s  = 0.9887 and the regression equation was y = 0.1505x + 0.0853. The radioactivity of 99m Tc- and 123 I-labeled radiopharmaceuticals in shielded syringes was accurately measured. It was suggested that the measuring shielded syringes could provide an estimate of the actual radioactivity., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Long-term field experiments have been carried out in the Chornobyl Exclusion zone to determine parameters describing technetium ( 99 Tc) transfer into five food plants (Lettuce, Radish, Wheat, Bean, and Potato) from four types of soil, namely Podzoluvisol, Greyzem, Phaeozem, and Chernozem. Technetium was added to the soils under field conditions in a pertechnetate form. In the first two years, soil type had little effect on Tc uptake by plants. In the first and second years after contamination, the concentration ratios (CR), defined as 99 Tc activity concentration in the crop (dry weight) divided by that in the soil (dry weight), for radish roots and lettuce leaves ranged from 60 to 210. For potato tubers, the CR was d 0.4-2.3, i.e., two orders of magnitude lower than for radish and lettuce, and for summer wheat grain it was lower at 0.6 ± 0.1. After 8-9 years, root uptake of 99 Tc by wheat decreased by 3-7 fold (CR from 0.016 ± 0.005 to 0.12 ± 0.034) and only 13-22 % of the total 99 Tc added remained in the upper 20 cm soil layers. The time taken for half of the added 99 Tc to be removed from the 20-cm arable soil layer due to vertical migration and transfer to plants was short at c. 2-3 years., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Recognizing the significance of SPECT in nuclear medicine and the pivotal role of fibroblast activation protein (FAP) in cancer diagnosis and therapy, this study focuses on the development of 99m Tc-labeled dimeric HF 2 with high tumor uptake and image contrast. The dimeric HF 2 was synthesized and radiolabeled with 99m Tc in one pot using various coligands (tricine, TPPTS, EDDA, and TPPMS) to yield [ 99m Tc]Tc-TPPTS-HF 2 , [ 99m Tc]Tc-EDDA-HF 2 , and [ 99m Tc]Tc-TPPMS-HF 2 dimers. SPECT imaging results indicated that [ 99m Tc]Tc-TPPTS-HF 2 exhibited higher tumor uptake and tumor-to-normal tissue (T/NT) ratio than [ 99m Tc]Tc-EDDA-HF 2 and [ 99m Tc]Tc-TPPMS-HF 2 . Notably, [ 99m Tc]Tc-TPPTS-HF 2 exhibited remarkable tumor accumulation and retention in HT-1080-FAP and U87-MG tumor-bearing mice, thereby surpassing the monomeric [ 99m Tc]Tc-TPPTS-HF. Moreover, [ 99m Tc]Tc-TPPTS-HF2 achieved acceptable T/NT ratios in the hepatocellular carcinoma patient-derived xenograft (HCC-PDX) model, which provided identifiable contrast and imaging quality. In conclusion, this study presents proof-of-concept research on 99m Tc-labeled FAP inhibitor dimers for the visualization of multiple tumor types. Among these candidate compounds, [ 99m Tc]Tc-TPPTS-HF 2 showed excellent clinical potential, thereby enriching the SPECT tracer toolbox.

Breast cancer is the most common diagnosed cancer, and the second cause of cancer death among women, worldwide. HER2 overexpression occurred in approximately 15% to 20% of breast cancers. Invasive biopsy method has been used for detection of HER2 overexpression. HER2-targeted imaging via an appropriate radionuclide is a promising method for sensitive and accurate identification of HER2 + primary and metastatic lesions. 99m Tc-anti-HER2 scFv can specifically target malignancies and be used for diagnosis of the cancer type and metastasis as well as treatment of breast cancer. We radiolabeled anti-HER2 scFv that was expressed in Escherichia coli and purified through Ni-NTA resin under native condition with 99m Tc-tricarbonyl formed from boranocarbonate. HER2-based ELISA, BCA, TLC, and HPLC were used in this study. In the current study, anti-HER2 scFv was lyophilized before radiolabeling. It was found that freeze-drying did not change the binding activity of anti-HER2 scFv to HER2. Results demonstrated direct anti-HER2 scFv radiolabeling by 99m Tc-tricarbonyl to hexahistidine sequence (His-tag) without any changes in biological activity and radiochemical purity of around 98%. Stability analysis revealed that 99m Tc-anti-HER2 scFv is stable for at least 24 h in PBS buffer, normal saline, human plasma proteins, and histidine solution., (© 2024 John Wiley & Sons Ltd.)

Tumor associated fibroblasts (TAFs) play a key role in tumor growth and metastatization. TAFs overexpress different biomarkers that are usually expressed at low levels in physiological conditions. Among them are the fibroblast growth factor receptors (FGFRs) that bind the fibroblast growth factors (FGFs). In particular, the overexpression of FGFR-2c in tumors has been associated with advanced clinical stages and increased metastatization. Here, we developed a non-invasive tool to evaluate, in vivo, the expression of FGFR-2c in metastatic cancer. This is based on 99m Tc-labelled FGF-2., Methods: 99m Tc-FGF-2 was tested in vitro and in vivo in mice bearing allografts of sarcoma cells. Images of 99m Tc-FGF-2 were acquired using a new portable high-resolution ultra-sensitive gamma camera for small animal imaging., Results: FGF-2 was labeled with high specific activity but low labelling efficiency, thus requiring post-labeling purification by gel-filtration chromatography. In vitro binding to 2C human keratinocytes showed a Kd of 3.36 × 10 -9 M. In mice bearing J774A.1 cell allografts, we observed high and rapid tumor uptake of 99m Tc-FGF-2 with a high Tumor/Blood ratio at 24 h post-injection (26.1 %ID/g and 12.9 %ID) with low kidney activity and moderate liver activity., Conclusions: we labeled FGF-2 with 99m Tc and showed nanomolar Kd in vitro with human keratinocytes expressing FGF-2 receptors. In mice, 99m Tc-FGF-2 rapidly and efficiently accumulated in tumors expressing FGF-2 receptors. This new radiopharmaceutical could be used in humans to image TAFs.

The main goal of this work was to elucidate the potential relevance of (radio)metal chelates of 99m Tc and Re targeting G-quadruplex structures for the design of new tools for cancer theranostics. 99m Tc provides the complexes with the ability to perform single-photon-emission computed tomography imaging studies, while the Re complexes should act as anticancer agents upon interaction with specific G4 DNA or RNA structures present in tumor tissues. Towards this goal, we have developed isostructural 99m Tc(I) and Re(I) tricarbonyl complexes anchored by a pyrazolyl-diamine (Pz) chelator carrying a pendant pyridostatin (PDS) fragment as the G4-binding motif. The interaction of the PDF-Pz-Re (8) complex with different G4-forming oligonucleotides was studied by circular dichroism, fluorescence spectroscopy and FRET-melting assays. The results showed that the Re complex retained the ability to bind and stabilize G4-structures from different DNA or RNA sequences, namely those present on the SRC proto-oncogene and telomeric RNA (TERRA sequence). PDF-Pz-Re (8) showed low to moderate cytotoxicity in PC3 and MCF-7 cancer cell lines, as typically observed for G4-binders. Biodistribution studies of the congener PDF-Pz- 99m Tc (12) in normal mice showed that the complex undergoes a fast blood clearance with a predominant hepatobiliary excretion, pointing also for a high in vitro stability., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Serotonergic (5-hydroxytryptamine; 5-HT) receptors play critical roles in neurological and psychological disorders such as schizophrenia, anxiety, depression, and Alzheimer's diseases. Therefore, it is particularly important to develop novel radioligands or modify the existing ones to identify the serotonergic receptors involved in psychiatric disorders. Among the 16 subtypes of serotonergic systems, only technetium-99m based radiopharmaceuticals have been evaluated for serotonin-1A (5-HT 1A ), serotonin-2A (5-HT 2A ), 5-HT 1A/7 heterodimers and serotonin receptor neurotransmitter (SERT). This review focuses on recent efforts in the design, synthesis and evaluation of 99m Tc-radioligands used for single photon emission computerized tomography (SPECT) imaging of serotonergic (5-HT) receptors. Additionally, the discussion will cover aspects such as chemical structure, in vitro/vivo stability, affinity toward serotonin receptors, blood-brain barrier permeation (BBB), and biodistribution study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Due to their favorable chemical features, Re and Tc complexes have been widely used for the development of new therapeutic agents and imaging probes to solve problems of biomedical relevance. This review provides an update of the most relevant research efforts towards the development of novel cancer theranostic agents using Re and Tc-based compounds interacting with specific DNA structures. This includes a variety of homometallic complexes, namely those containing M(CO) 3 (M=Re, Tc) moieties, that exhibit different modes of interaction with DNA, such as covalent binding, intercalation, groove binding or G-quadruplex DNA binding. Additionally, heterometallic complexes, designed to potentiate synergistic effects of different metal centers to improve DNA-targeting, cytotoxicity and fluorescence properties, are also reviewed. Particular attention is also given to 99m Tc- and 188 Re-labeled oligonucleotides that have been widely explored to develop imaging and therapeutic radiopharmaceuticals through the in vivo hybridization with a specific complementary DNA or RNA target sequence to provide useful molecular tools in precision medicine for cancer diagnosis and treatment. Finally, the need for further improvement of DNA-targeted Re and Tc-based compounds as potential therapeutic and diagnostic agents is highlighted, and future directions are discussed., (© 2023 Wiley-VCH GmbH.)

Aβ 42 plaque formation is one of the preliminary pathologic events that occur post traumatic brain injury (TBI) which is also among the most noteworthy hallmarks of AD. Their pre symptomatic detection is therefore vital for better disease management. Chalcone-picolinic acid chelator derivative, 6-({[(6-carboxypyridin-2-yl)methyl](2-{4-[(2E)-3-[4-(dimethyl amino)phenyl]prop-2-enoyl]phenoxy}ethyl)amino}methyl)pyridine-2-carboxylic acid, Py-chal was synthesized to selectively identify amyloid plaques formed post head trauma using SPECT imaging by stable complexation to 99m Tc with > 97% efficiency without compromising amyloid specificity. The binding potential of the Py-chal ligand to amyloid plaques remained high as confirmed by in vitro binding assay and photophysical spectra. Further, the Py-chal complex stained amyloid aggregates in the brain sections of rmTBI mice model. In vivo scintigraphy in TBI mice model displayed high uptake followed by high retention while the healthy rabbits displayed higher brain uptake followed by a rapid washout attributed to absence of amyloid plaques. Higher uptake in brain of TBI model was also confirmed by ex vivo biodistribution analysis wherein brain uptake of 3.38 ± 0.2% ID/g at 2 min p.i. was observed for TBI mice model. This was followed by prolonged retention and more than twofold higher activity as compared to sham mice brain. This preliminary data suggests the specificity of the radiotracer for amyloid detection post head trauma and applicability of 99m Tc labeled Py-chal complex for TBI-induced β-amyloid SPECT imaging., (© 2024. The Author(s), under exclusive licence to Society for Biological Inorganic Chemistry (SBIC).)

Fibroblast activation protein (FAP), which is expressed on the cell membranes of fibroblasts in most solid tumors, has become an important target for tumor diagnosis and treatment. However, previously reported 99m Tc-labeled FAPI-04 complexes have high blood uptake, limiting their use in the clinic. In this work, six 99m Tc-labeled FAPI-46 derivatives with different linkers (different amino acids, peptides, or polyethylene glycol) were prepared and evaluated. They had good in vitro stability, hydrophilicity, and good specificity for FAP. The biodistribution and MicroSPECT images revealed that they all had high specific tumor uptake for FAP, and their blood uptake was significantly decreased. Among them, [ 99m Tc]Tc-6-1 exhibited the highest target-to-nontarget ratios (tumor/blood: 6.06 ± 1.19; tumor/muscle: 10.26 ± 0.44) and good tumor uptake (16.15 ± 0.83%ID/g), which also had significantly high affinity for FAP, good in vivo stability, and safety. Therefore, [ 99m Tc]Tc-6-1 holds great potential as a promising molecular tracer for FAP tumor imaging.

Background: The 5-hydroxytryptamine receptor (5-HTR) family includes seven classes of receptors. The 5-HT 7 R is the newest member of this family and contributes to different physiological and pathological processes. As a pathology, glioblastoma multiform (GBM) overexpresses 5-HT 7 R; hence, this study aims to develop radiolabeled aryl piperazine derivatives as 5-HT 7 R imaging agents.  METHODS: Compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were radiolabeled with fac-[ 99m Tc(CO) 3 (H 2 O) 3 ] + and 99m Tc(CO) 3 -[6] and 99m Tc(CO) 3 -[7] were obtained with high radiochemical purity (RCP > 94%). The stability of the radiotracers was evaluated in both saline and mouse serum. Specific binding on different cell lines including U-87 MG, MCF-7, SKBR3, and HT-29 was performed. The biodistribution of these radiotracers was evaluated in normal and U-87 MG Xenografted models. Finally, 99m Tc(CO) 3 -[6] and 99m Tc(CO) 3 -[7] were applied for in vivo imaging in U-87 MG Xenografted models., Results: Specific binding study indicates that 99m Tc(CO) 3 -[6] and 99m Tc(CO) 3 -[7] can recognize 5-HT 7 R of U87-MG cell line. The biodistribution study in normal mice indicates that the brain uptake of 99m Tc(CO) 3 -[6] and 99m Tc(CO) 3 -[7] is the highest at 30 min post-injection (0.8 ± 0.25 and 0.64 ± 0.18%ID/g, respectively). The data of the biodistribution study in the U87-MG xenograft model revealed that these radiotracers could accumulate in the tumor site, and the highest tumor uptake was observed at 60 min post-injection (3.38 ± 0.65 and 3.27 ± 0.5%ID/g, respectively). The injection of pimozide can block the tumor's radiotracer uptake, indicating the binding of these radiotracers to the 5-HT 7 R. The imaging study in the xenograft model also confirms the biodistribution data. The acquired images clearly show the tumor site, and the tumor-to-muscle ratio for 99m Tc(CO) 3 -[6] and 99m Tc(CO) 3 -[7] at 60 min was 3.33 and 3.88, respectively.  CONCLUSIONS: 99m Tc(CO) 3 -[6] and 99m Tc(CO) 3 -[7] can visualize tumor in the U87-MG xenograft model  due to their affinity toward 5-HT 7 R., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Background: Angiogenesis is a process that many tumors depend on for growth, development, and metastasis. Vascular endothelial growth factor (VEGF) is one of the major players in tumor angiogenesis in several tumor types, including melanoma. VEGF inhibition is achieved by bevacizumab, a humanized monoclonal antibody that binds with high affinity to VEGF and prevents its function. In order to successfully enable in vivo VEGF expression imaging in a murine melanoma model, we previously labeled bevacizumab with [ 99m Tc]Tc. We observed that this was feasible, but it had prolonged blood circulation and delayed tumor uptake., Objective: The aim of this study was to develop a radiolabeled Fab bevacizumab fragment, [ 99m Tc]Tc-HYNICFab( bevacizumab), for non-invasive in vivo VEGF expression molecular imaging., Methods: Flow cytometry was used to examine VEGF presence in the murine melanoma cell line (B16-F10). Bevacizumab was digested with papain for six hours at 37°C to produce Fab(bevacizumab), which was then conjugated to NHS-HYNIC-Tfa for radiolabeling with [ 99m Tc]Tc. Stability and binding affinity assays were also evaluated. Biodistribution and single photon emission computed tomography/computed tomography (SPECT/CT) were performed at 1, 3, and 6 h (n = 4) after injection of [ 99m Tc]Tc-HYNIC-Fab(Bevacizumab) in normal and B16-F10 tumor-bearing C57Bl/6J mice., Results: Using flow cytometry, it was shown that the B16-F10 murine melanoma cell line has intracellular VEGF expression. Papain incubation resulted in the complete digestion of bevacizumab with good purity and homogeneity. The radiolabeling yield of [ 99m Tc]Tc-HYNIC-Fab(bevacizumab) was 85.00 ± 6.06%, with a specific activity of 291.87 ± 18.84 MBq/mg (n=3), showing in vitro stability. Binding assays demonstrated significant intracellular in vitro VEGF expression. Fast blood clearance and high kidney and tumor uptake were observed in biodistribution and SPECT/CT studies., Conclusions: We present the development and evaluation of [ 99m Tc]Tc-HYNIC-Fab(bevacizumab), a novel molecular VEGF expression imaging agent that may be used for precision medicine in melanoma and potentially in other VEGF-expressing tumors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Acetaminosalol labeling reaction with technetium-99m was optimized, and the radiocomplex was obtained in a high radiochemical yield of 98.9 ± 0.6% and high stability (>30 h). The tracer was characterized, and its binding to the PPARγ receptor was assessed in silico. To reduce radiation exposure to non-target organs and increase accumulation in the colon, the tracer was formulated as pH-sensitive microspheres with a mean particle size of 201 ± 2.1 μm, a polydispersity index of 0.18, a 25.3 ± 3.6 zeta potential, and 98.6 ± 0.33% entrapment efficiency. The system suitability was assessed in vivo in normal and ulcerative rats, and the biodistribution profile in the colon showed 56.5 ± 1.4% localization within 4 h. Blocking study suggested the selectivity of the tracer to the target receptor. Overall, the reported data encouraged the potential use of the labeled microspheres to target ulcerative colitis., (© 2023 John Wiley & Sons Ltd.)

Introduction: C-X-C Chemokine receptor type 4 (CXCR4) is often overexpressed or overactivated in different types and stages of cancer disease. Therefore, it is considered a promising target for imaging and early detection of primary tumors and metastasis. In the present research, a new cyclo-peptide radiolabelled with 99m Tc, 99m Tc-Cyclo [D-Phe-D-Tyr-Lys (HYNIC)- D-Arg-2-Nal-Gly-Lys(iPr)], was designed based on the parental LY251029 peptide, as a potential in vivo imaging agent of CXCR4-expressing tumors., Methods: The radioligand was successfully prepared using the method of Fmoc solid-phase peptide synthesis and was evaluated in biological assessment. Molecular docking findings revealed high affinity (binding energy of -9.7 kcal/mol) and effective interaction of Cyclo [D-Phe- D-Tyr-Lys (HYNIC)-D-Arg-2-Nal-Gly-Lys(iPr)] in the binding pocket of CXCR4 receptor (PDB code: 3OE0) as well., Result: The synthesized peptide and its purity were assessed by both reversed-phase high-performance liquid chromatography (RP-HPLC) and mass spectroscopy. High stability (95%, n = 3) in human serum and favorable affinity (Kd = 28.70 ± 13.56 nM and Bmax = 1.896 ± 0.123 fmol/mg protein) in the B16-F10 cell line resulted. Biodistribution evaluation findings and planar image interpretation of mice both showed high affinity and selectivity of the radiotracer to the CXCR4 receptors., Conclusion: Therefore, the findings indicate this designed radioligand could be used as a potential SPECT imaging agent in highly proliferated CXCR4 receptor tumors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, 99m Tc, and the therapeutic radionuclide, 188 Re, can potentially enable receptor-targeted "theranostic" treatment of disease. Here we show that Pt(0)-catalyzed hydrophosphination reactions are well-suited to the derivatization of diphosphines with biomolecular moieties enabling the efficient synthesis of ligands of the type Ph 2 PCH 2 CH 2 P(CH 2 CH 2 -Glc) 2 ( L , where Glc = a glucose moiety) using the readily accessible Ph 2 PCH 2 CH 2 PH 2 and acryl derivatives. It is shown that hydrophosphination of an acrylate derivative of a deprotected glucose can be carried out in aqueous media. Furthermore, the resulting glucose-chelator conjugates can be radiolabeled with either 99m Tc(V) or 188 Re(V) in high radiochemical yields (>95%), to furnish separable mixtures of cis - and trans -[M(O) 2 L 2 ] + (M = Tc, Re). Single photon emission computed tomography (SPECT) imaging and ex vivo biodistribution in healthy mice show that each isomer possesses favorable pharmacokinetic properties, with rapid clearance from blood circulation via a renal pathway. Both cis -[ 99m Tc(O) 2 L 2 ] + and trans -[ 99m Tc(O) 2 L 2 ] + exhibit high stability in serum. This new class of functionalized diphosphine chelators has the potential to provide access to receptor-targeted dual diagnostic/therapeutic pairs of radiopharmaceutical agents, for molecular 99m Tc SPECT imaging and 188 Re systemic radiotherapy.

Bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators have demonstrated utility in nuclear medicine. In particular, the 64 Cu 2+ complexes have been extensively developed for hypoxia imaging and molecular imaging of peptide and protein markers of disease. However, the chemistry and application of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators in combination with 99m Tc, the most widely used radionuclide in nuclear medicine, is underexplored. Herein, a series of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators were radiolabeled with nitrido-technetium-99m in an optimized one-pot synthesis from [ 99m Tc]TcO 4 - . Optimization of the radiochemical syntheses allowed for production of the complexes in >90% radiochemical conversion with apparent molar activities of 3.3-5 GBq/μmol. Competition experiments demonstrated the excellent stability of the complexes. The nitrido-technetium-99 complexes were synthesized, and the chemical identities were investigated using mass spectrometry, spectroscopy, and density functional theory calculations. Complexation of nitrido-rhenium(V) was achieved with the N 4 -dialkylated bis(thiosemicarbazones). Planar imaging and ex vivo biodistribution studies of the five 99m Tc complexes were conducted on healthy BALB/c mice to determine in vivo behavior. The lipophilic nature of the complexes resulted in uptake of 1.6-5.7% ID g -1 in the brain at 2 min postinjection and retention of 0.4-1.7% ID g -1 at 15 min postinjection. The stability of the complexes and the biodistribution data demonstrate that these chelators are ideal platforms for future production of radiopharmaceutical candidates.

The discovery and development of new 99m Tc-based radiopharmaceuticals or labeled drugs in general is based on innovative, pure chemistry and subsequent, application-targeted research. This was the case for all currently clinically applied imaging agents. Most of them were market-introduced some 20 years ago, and the few more recent ones are based on even older chemistry, albeit technetium chemistry has made substantial progress over the last 20 years. This progress though is not mirrored by new molecular imaging agents and is even accompanied by a steady decrease in the number of groups active in pure and applied technetium chemistry, a contrast to the trends in most other fields in which d-elements play a central role. The decrease in research with technetium has been partly counterbalanced by a strong increase of research activities with homologous, cold rhenium compounds for therapy, disclosing in the future eventually a quite unique opportunity for theranostics. This Viewpoint analyzes the pathways that led to radiopharmaceuticals in the past and their underlying fundamental contributions. It attempts to tackle the question of why new chemistry still does not lead to new imaging agents, i.e., the question of whether pure technetium chemistry is still needed at all.

Radionuclide imaging using radiolabeled inhibitors of prostate-specific membrane antigen (PSMA) can be used for the staging of prostate cancer. Previously, we optimized the Glu-urea-Lys binding moiety using a linker structure containing 2-napththyl-L-alanine and L-tyrosine. We have now designed a molecule that contains mercaptoacetyl-triglutamate chelator for labeling with Tc-99m (designated as BQ0413). The purpose of this study was to evaluate the imaging properties of [ 99m Tc]Tc-BQ0413. PSMA-transfected PC3-pip cells were used to evaluate the specificity and affinity of [ 99m Tc]Tc-BQ0413 binding in vitro. PC3-pip tumor-bearing BALB/C nu/nu mice were used as an in vivo model. [ 99m Tc]Tc-BQ0413 bound specifically to PC3-pip cells with an affinity of 33 ± 15 pM. In tumor-bearing mice, the tumor uptake of [ 99m Tc]Tc-BQ0413 (38 ± 6 %IA/g in PC3-pip 3 h after the injection of 40 pmol) was dependent on PSMA expression (3 ± 2 %IA/g and 0.9 ± 0.3 %IA/g in PSMA-negative PC-3 and SKOV-3 tumors, respectively). We show that both unlabeled BQ0413 and the commonly used binder PSMA-11 enable the blocking of [ 99m Tc]Tc-BQ0413 uptake in normal PSMA-expressing tissues without blocking the uptake in tumors. This resulted in an appreciable increase in tumor-to-organ ratios. At the same injected mass (5 nmol), the use of BQ0413 was more efficient in suppressing renal uptake than the use of PSMA-11. In conclusion, [ 99m Tc]Tc-BQ0413 is a promising probe for the visualization of PSMA-positive lesions using single-photon emission computed tomography (SPECT).

Infectious diseases caused by bacteria that have become resistant to antibiotics have increased in prevalence, necessitating new methods for their diagnosis and treatment. The aim of this study was to compare the efficacy of synthetic ciprofloxacin to that of organic ciprofloxacin produced by cave microorganisms, as well as to evaluate the feasibility of using organic ciprofloxacin radiolabeled with technetium-99m as an imaging agent. Organic ciprofloxacin produced by cave bacteria isolated from sediment taken from the dark zone of Antalya's "Yark Sinkhole," (Turkey's 14th deepest cave), was purified using high-performance liquid chromatography. Purified organic ciprofloxacin and standard ciprofloxacin were radiolabeled with technetium-99m (99mTc), and their uptake by pathogenic microorganisms as well as potential as an imaging agent were examined. According to thin-layer radiochromatography, radiolabeling efficiencies were 98.99 ± 0.34 (n = 7) and 91.25 ± 1.84 (n = 7) for radiolabeled organic ciprofloxacin and standard ciprofloxacin respectively. The binding efficiency of radiolabeled organic ciprofloxacin at the 240th minute was higher compared with radiolabeled standard ciprofloxacin, especially with P.aeruginosa, MRSA, VRE and E.coli. The results demonstrate that radiolabeling with 99mTc does not alter the biological behavior of organic ciprofloxacin, and radiolabeled organic ciprofloxacin has potential as an imaging agent for the detection of bacterial infection. The original value of the study is the monitoring of the antibiofilm effects of untouched cave-derived organic antibiotics by radiolabeling with a radionuclide., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Karatay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The pursuit of molecular imaging for tumors has led to endeavors focused on targeting epidermal growth factor receptors (EGFR) through monoclonal antibodies or radionuclide-labelled EGF analogs with 99m Tc, 111 In, or 131 I. In this context, various 99m Tc-labeled EGFR inhibitors using quinazoline structures have been reported based on the so-called pendant approach and on two types of complexes and labelling strategies: "4 + 1" mixed ligand complexes and fac -tricarbonyl complexes. Apart from this approach, which alters lead structures by linking pharmacophores to chelator frameworks through different connectors, the integrated incorporation of topoisomerase and tyrosine kinase inhibitors into Re and 99m Tc complexes has not been explored. Here we present [M(η 6 -inhibitor) 2 ] + (M = Re, 99m Tc) and [Re(η 6 -bz)(η 6 -inhibitor)] + complexes, where the core structure of an EGFR tyrosine kinase inhibitor binds directly to the metal center. These complexes exhibit potential for tumor imaging: initial biological investigations highlight the influence of one versus two bound inhibitors on the metal center.

Brain abscess is a life-threatening condition that requires a timely and accurate diagnosis. In this study, linezolid, an oxazolidinone antibiotic, was labeled with technetium-99m according to the stannous chloride method. The labeling reaction factors were studied and optimized to achieve a high yield (97.4 ± 2.3%). The 99m Tc-linezolid was radio- and physico-chemically characterized to assess its suitability as a radiopharmaceutical for the brain. In-silico docking to target peptidyltransferase showed an optimal binding fit (energy = -66.6 Kcal/mol). The complex was biologically evaluated in-vitro using binding assays in alive and heat-killed bacteria and in-vivo in an MRSA brain infection model. All results suggested that the labeled complex could potentially be a new nuclear imaging agent to diagnose and localize brain abscesses specifically., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The Glu-Urea-Lys (EUK) pharmacophore as prostate-specific membrane antigen (PSMA)-targeted ligand was synthesized, radiolabeled with 99m Tc-tricarbonyl-imidazole-BPS chelation system, and biological activities were evaluated. The strategy [2 + 1] ligand is applied for tricarbonyl labeling. (5-imidazole-1-yl)pentanoic acid as a monodentate ligand and bathophenanthroline disulfonate (BPS) as a bidentate ligand formed a chelate system with 99m Tc-tricarbonyl. EUK-pentanoic acid-imidazole and EUK were evaluated for PSMA active site using AutoDock 4 software. Materials and Methods: EUK-pentanoic acid-imidazole was synthesized in two steps. BPS was radiolabeled with 99m Tc-tricarbonyl at 100°C for 30 min. The purified 99m Tc(CO) 3 (H 2 O)BPS was used to radiolabel EUK-pentanoic acid-imidazole at 100°C, 30 min. Radiochemical purity, Log P, and stability studies were carried out within 24 h. Affinity of 99m Tc(CO) 3 BPS-imidazole-EUK was performed in the saturation binding studies using LNCaP cells at 37°C for 1 h with a range of 0.001-1000 nM radiolabeled compound range. Internalization studies were performed in LNCaP cells with 1000 nM radiolabeled compound incubated for (0-2) h at 37°C. Biodistribution was studied in normal male Balb/c mice. The artificial intelligence predicts the uptake of radiolabeled compound in tumor. Results: The structures of synthesized compounds were confirmed by mass spectroscopy. Radiochemical purity, Log P, and protein binding were ≥95%, -0.2%, and 23%, respectively. The radiolabeled compound was stable in saline and human plasma within 24 h with radiochemical purity ≥90%. There was no release of 99m Tc within 4 h in competition with histidine. The affinity was 82 ± 26.38 nM, and the activity increased inside the cells over time. Biodistribution studies showed radioactivity accumulation in kidneys less than 99m Tc-HYNIC-PSMA. There was a moderate accumulation of radioactivity in the liver and intestine. Conclusion: Based on the results, 99m Tc(CO) 3 BPS-imidazole-EUK can potentially be used as an imaging agent for studies at prostate bed and distal areas. The chelate system can be potentially labeled with rhenium for imaging studies (fluorescent or scintigraphy) and therapy.

B7-H3 (CD276), an immune checkpoint protein, is a promising molecular target for immune therapy of malignant tumours. Sufficient B7-H3 expression level is a precondition for successful therapy. Radionuclide molecular imaging is a powerful technique for visualization of expression levels of molecular targets in vivo. Use of small radiolabelled targeting proteins would enable high-contrast radionuclide imaging of molecular targets if adequate binding affinity and specificity of an imaging probe could be provided. Affibody molecules, small engineered affinity proteins based on a non-immunoglobulin scaffold, have demonstrated an appreciable potential in radionuclide imaging. Proof-of principle of radionuclide visualization of expression levels of B7-H3 in vivo was demonstrated using the [ 99m Tc]Tc-AC12-GGGC Affibody molecule. We performed an affinity maturation of AC12, enabling selection of clones with higher affinity. Three most promising clones were expressed with a -GGGC (triglycine-cysteine) chelating sequence at the C-terminus and labelled with technetium-99m ( 99m Tc). 99m Tc-labelled conjugates bound to B7-H3-expressing cells specifically in vitro and in vivo. Biodistribution in mice bearing B7-H3-expressing SKOV-3 xenografts demonstrated improved imaging properties of the new conjugates compared with the parental variant [ 99m Tc]Tc-AC12-GGGC. [ 99m Tc]Tc-SYNT-179 provided the strongest improvement of tumour-to-organ ratios. Thus, affinity maturation of B7-H3 Affibody molecules could improve biodistribution and targeting properties for imaging of B7-H3-expressing tumours., Competing Interests: Declaration of competing interest V.T., and A.O. are minority shareholders (own stock) in Affibody AB. M.O., S. K., I.K., E.R., and F.Y.F., are employees of Affibody AB. E.A.B., T.X., Y.L., and E.P., declare no potential conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Technetium-99m generators employing a technetium-selective stationary phase are a chromatographic instrument developed for use with 99 Mo having low specific activity (LSA); particularly, 99 Mo produced by electron accelerators. This paper presents a mathematical description of technetium-selective chromatographic (TSC) 99m Tc separation and analyzes its compatibility with LSA 99 Mo. We developed a theoretical formula for TSC 99m Tc separation by discretizing its pertechnetate selectivity, and validated it using an electron linear accelerator and activated carbon-based TSC (AC-TSC) 99m Tc generators. We confirmed that the activity concentration of 99m Tc obtained from a TSC 99m Tc generator can be calculated directly from its input 99 Mo activity regardless of the 99 Mo specific activity. The formula corroborates that TSC 99m Tc separation is compatible with LSA 99 Mo, and has a practical application in estimating the number of TSC 99m Tc generators required for 99m Tc demand of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The development of new drugs that can specifically screen tumors is a global need. When it comes to lung cancer, which is the second main cause of cancer-related deaths, early detection of lung tumors using appropriate imaging is very important. In this study, gemcitabine hydrochloride (GCH) was radiolabeled with [ 99m Tc]Tc under different conditions (changing reducing agent, antioxidant agent, incubation time, pH, [ 99m Tc]Tc activity) and radiolabeling activity (quality control) using Radio Thin Layer Chromatography and paper electrophoresis. The results showed that the most stable complex ([ 99m Tc]Tc-GCH) was prepared using 0.015 mg of stannous chloride as a reducing agent, 0.01 mg of ascorbic acid as an antioxidant and 37 MBq activity at pH 7.4 after 15 min of incubation time. The complex remained stable for 6 h. Cell incorporation studies showed a six-fold higher uptake of [ 99m Tc]Tc-GCH in cancer (A-549) cells (38.42 ± 1.53) than healthy (L-929) cells (6.11 ± 0.17) have shown that it can. In addition, the different behaviors of R/H-[ 99m Tc]Tc confirmed the specificity of this newly developed radiopharmaceutical. Although these studies are preliminary, it has been concluded that [ 99m Tc]Tc-GCH may be a candidate drug for use in nuclear medicine, particularly in the diagnosis of lung cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Achieving target specific delivery of chemotherapeutics in metastatic skeletal lesions remains a major challenge. Towards this, a dual drug loaded, radiolabeled multi-trigger responsive nanoparticles having partially oxidized hyaluronate (HADA) conjugated to alendronate shell and palmitic acid core were developed. While the hydrophobic drug, celecoxib was encapsulated in the palmitic acid core, the hydrophilic drug, doxorubicin hydrochloride was linked to the shell via a pH responsive imine linkage. Hydroxyapatite binding studies showed affinity of alendronate conjugated HADA nanoparticles to bones. Enhanced cellular uptake of the nanoparticles was achieved via HADA-CD44 receptor binding. HADA nanoparticles demonstrated trigger responsive release of encapsulated drugs in the presence of hyaluronidase, pH and glucose, present in excess in the tumor microenvironment. Efficacy of the nanoparticles for combination chemotherapy was established by >10-fold reduction in IC 50 of drug loaded particles with a combination index of 0.453, as compared to free drugs in MDA-MB-231 cells. The nanoparticles could be radiolabeled with the gamma emitting radioisotope technetium-99m ( 99m Tc) through a simple, 'chelator free', procedure with excellent radiochemical purity (RCP) (>90 %) and in vitro stability. 99m Tc-labeled drug loaded nanoparticles reported herein constitutes a promising theranostic agent to target metastatic bone lesions. STATEMENT OF HYPOTHESES: Technetium-99m labeled, alendronate conjugated, dual targeting, tumor responsive, hyaluronate nanoparticle for tumor specific drug release and enhanced therapeutic effect, with real-time in vivo monitoring., Competing Interests: Declaration of competing interest Authors declare no competing financial interests or personal relationships to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Application of nanoradiopharmaceuticals for molecular imaging has gained worldwide importance for their multifaceted potentials focusing on providing a safe and cost-effective approach. Biodistribution studies on such species are capable of bringing nanomedicine to patients. Current therapeutically available labeling strategies suffer from different limitations, including off-target cytotoxicity and radiolabel release over time. Poly(lactic-co-glycolic acid)(PLGA) nanoparticles are biodegradable carriers for a variety of contrast agents that can be employed in medicine with high loading capacity for multimodal imaging agents. Here, glutamine-conjugated PLGA polymers were used to construct polymeric nanoparticles (G-PNP) similar to unconjugated PLGA nanoparticles (PNP)s formulated for ex vivo cell labeling and in vivo tumor scintigraphy studies. G-PNP/PNP, characterized by Fourier-transform infrared, atomic-force-microscopy, particle-size, and zeta-potential studies, were biocompatible as evaluated by MTT assay. G-PNPs were radiolabeled with 99m technetium ( 99m Tc) by borohydrite reduction. G-PNPs demonstrated higher cellular uptake than PNPs, with no major cytotoxicity. Radiochemical purity indicated that 99m Tc labeled G-PNP ( 99m Tc-G-PNP) can form a stable complex with substantial stability in serum with respect to time. Imaging studies showed that 99m Tc-G-PNP significantly accumulated at the C6 glioma cell induced tumor-site in rats. Thus, 99m Tc-G-PNP demonstrated favorable characteristics and imaging potential which may make it a promising tumor imaging nanoprobe as a nanoradiopharmaceutical.

Folate receptors (FRs) are known to be over-expressed in several human malignancies and therefore serve as an important target for small radiolabeled folate derivatives for non-invasive imaging of tumor, which is an important tool for future treatment recourse. In the present article, we report the synthesis of a new 99m Tc-labeled radiotracer for the aforementioned application following the well-established 99m Tc-'4+1' chemistry. Formation of the desired [ 99m Tc]Tc-complex with >95% radiochemical purity was confirmed by radio-HPLC and its structure was ascertained by characterizing a natural rhenium analogue of the said complex. Although the ligand exhibited a weaker affinity towards FRs compared to native folic acid (IC50 8.09 µM vs 29.46 nM), the 99m Tc-labeled complex was found to bind folate receptor-positive KB cells with high specificity (∼90%). Similar studies in a folate receptor negative cell line viz. A549 further corroborated the receptor-specificity of the synthesized complex. In vivo studies in KB tumor xenograft showed moderate uptake of ∼2.6% upto 3 h post-injection with high specificity (∼80%). The favorable features observed warrant further screening of the current design towards achieving an improved molecular probe for the said application., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The chemistry of technetium ( t 1/2 ( 99 Tc) = 2.11 × 10 5 years) is of particular importance in the context of nuclear waste disposal and historic contaminated sites. Polycarboxylate ligands may be present in some sites and are potentially capable of strong complexing interactions, thus increasing the solubility and mobility of 99 Tc under environmentally relevant conditions. This work aimed to determine the impact of five organic complexing ligands [L = oxalate, phthalate, citrate, nitrilotriacetate (NTA), and ethylenediaminetetraacetate (EDTA)] under anoxic, alkaline conditions (pH ≈ 9-13) on the solubility of technetium. X-ray absorption spectroscopy confirmed that TcO 2 (am,hyd) remained the solubility-controlling solid phase in undersaturation solubility experiments. Ligands with maximum coordination numbers (CN) ≥ 3 (EDTA, NTA, and citrate) exhibited an increase in solubility from pH 9 to 11, while ligands with CN ≤ 2 (oxalate and phthalate) at all investigated pH and CN ≥ 3 at pH ≈ 13 were outcompeted by hydrolysis reactions. Though most available thermodynamic values were determined under acidic conditions, these models satisfactorily explained high-pH undersaturation solubility of technetium for citrate and NTA, whereas experimental data for Tc(IV)-EDTA were highly overestimated. This work illustrates the predominance of hydrolysis under hyperalkaline conditions and provides experimental support for existing thermodynamic models of Tc-L except Tc-EDTA, which requires further research regarding aqueous speciation and solubility.