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The 2‐nitroimidazole based 99mTc‐radiopharmaceuticals are widely explored for imaging tumor hypoxia. Radiopharmaceuticals for targeting hypoxia are often lipophilic and therefore, show significant uptake in liver and other vital organs. In this context, lipophilic radiopharmaceuticals with design features enabling faster clearance from liver may be more desirable. A dipicolylamine‐NCS bifunctional chelator that could generate a thiourea‐bridge up on conjugation to primary amine bearing molecule was used to synthesize a 2‐nitroimidazole‐dipicolyl amine ligand for radiolabeling with 99mTc(CO)3 core. Corresponding Re(CO)3‐analogue was prepared to establish the structure of 2‐nitroimidazole‐99mTc(CO)3 complex prepared in trace level. The 2‐nitroimidazole‐99mTc(CO)3 complex showed a hypoxic to normoxic ratio of ~2.5 in CHO cells at 3 h. In vivo, the complex showed accumulation and retention in tumor with high tumor to blood and tumor to muscle ratio. The study demonstrated the utility of metabolizable thiourea‐bridge in 2‐nitroimidazole‐99mTc(CO)3 complex in inducing faster clearance of the radiotracer from liver. The dipicolylamine‐NCS bifunctional chelator reported herein can also be used for radiolabeling other class of target specific molecules with 99mTc(CO)3 core. [ABSTRACT FROM AUTHOR]

Simple Summary: Nuclear medicine imaging techniques consist of acquiring images after intravenous administration of a small dose of radioactive molecules. Different nuclear medicine techniques are available in the horse. Scintigraphy provides two-dimensional images and has been used for the detection of bone injuries in horses since the late 1970s. This was at the time the only alternative to radiographs to detect bone issues in horses. As other imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) have developed, the role of scintigraphy in horses has reduced. Scintigraphy remains, however, commonly used in racehorses to detect stress injuries and is also used in other horses to image larger body areas or even the whole body of a horse. In the last 10 years, positron emission tomography (PET) has become available in horses and provides higher resolution three-dimensional images. PET shows promising applications by either replacing the use of scintigraphy for the smaller areas of the limbs or by adding useful information to other imaging techniques. PET allows detection of some injuries prior to their identification with CT or MRI and also helps decide if an injury is active or represents an old scar. Scintigraphy and Positron Emission Tomography (PET) are both nuclear medicine imaging techniques, providing functional information of the imaged areas. Scintigraphy is a two-dimensional projected imaging technique that was introduced in equine imaging in the late 1970s. Scintigraphy allows imaging of large body parts and can cover multiple areas, remaining the only technique commonly used in horses for whole body imaging. PET is a cross-sectional imaging technique, first used in horses in 2015, allowing higher resolution three-dimensional functional imaging of the equine distal limb. This manuscript will cover current use and values of these two modalities in equine lameness diagnosis. [ABSTRACT FROM AUTHOR]

In this study, a new nano-structure, N,P-doped graphene quantum dots (N,P-GQDs), were synthesized as multipurpose imaging agent for performing scintigraphy and magnetic resonance imaging (MRI). Some standard characterization methods were used to identify the nano-structure. In vitro cytotoxicity evaluation using MTT assay revealed that N,P-GQDs nanoparticles had no significant cytotoxicity after 24 and 48 h against normal (MCF-10A) and cancerous (MCF 7) human breast cell line in concentration up to 200 μg/mL. The N,P-GQDs were radiolabeled with Technetium-99m as 99mTc-(N,P-GQDs) and the radiochemical purity was assayed by ITLC concluding RCP ≥ 95 %. The passing of 99mTc-(N,P-GQDs) through 0.1 µm filter demonstrated that 70.8 % of particles were <0.1 µm. In order to perform scintigraphy, the 99mTc-(N,P-GQDs) were injected to female healthy Wistar rats. The results showed that the radio-complex was captured and eliminated just by kidneys. Moreover, in vitro T1-weighted phantom MRI imaging showed that the N,P-GQDs have proper relaxivity in comparison to Dotarem® as a clinically available contrast agent. The results showed that the N,P-GQDs have potential to be considered as a novel and encouraging agent for both molecular MRI and nuclear medicine imagings. [ABSTRACT FROM AUTHOR]

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 99mTc‐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 99mTc, the optimum radiolabeling condition was determined as 200 ppm SnCl2 and 0.5 mg ascorbic acid, and both 99mTc‐MS/TOFA‐9 and 99mTc‐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. [ABSTRACT FROM AUTHOR]

In this study, we compared in vitro and in vivo results of the 99mTc-labeled HYNIC-KRWrNM in the presence of Tricine/EDDA and Tricine/Nicotinic acid (NA) as two co-ligand systems ([99mTc]Tc-M-7 and [99mTc]Tc-M-6, respectively). The dissociation constant (Kd) value of [99mTc]Tc-M-6 was 7.1 ± 2.3 nM for U87-MG cell line (glioblastoma). Based on biodistribution studies, the tumor-to-muscle ratio of [99mTc]Tc-M-6 was 8.77 and 11.33 at 1.5 and 4 h after injection, respectively. Finally, target-to-background ratio in the planar gamma image was 12.03 at 4 h after injection. By comparison, our experimental results showed that substitution of EDDA by Nicotinic acid in the 99mTc-labeling of HYNIC-KRWrNM led to the formation of an improved tumor-targeting peptide. This improved radio-peptide can be a potential agent for the diagnosis of integrin αvβ3-positive tumors. [ABSTRACT FROM AUTHOR]

With the development of PD-1/PD-L1 immune checkpoint inhibitor therapy, the ability to monitor PD-L1 expression in the tumor microenvironment is important for guiding therapy. This study was performed to develop a novel radiotracer with optimal pharmacokinetic properties to reflect PD-L1 expression in vivo via single-photon emission computed tomography (SPECT) imaging. [99mTc]Tc-HYNIC-WL12-tricine/M (M = TPPTS, PDA, ISONIC, 4-PSA) complexes with high radiochemical purity (>97%) and suitable molar activity (from 100.5 GBq/μmol to 300 GBq/μmol) were prepared through a kit preparation process. All 99mTc-labeled HYNIC-WL12 radiotracers displayed good in vitro stability for 4 h. The affinity and specificity of the four radiotracers for PD-L1 were demonstrated both in vitro and in vivo. The results of biodistribution studies displayed that the pharmacokinetics of the 99mTc-HYNIC-conjugated radiotracers were significantly influenced by the coligands of the radiotracers. Among them, [99mTc]Tc-HYNIC-WL12-tricine/ISONIC exhibited the optimal pharmacokinetic properties (t1/2α = 8.55 min, t1/2β = 54.05 min), including the fastest clearance in nontarget tissues, highest tumor-to-background contrast (e.g., tumor-to-muscle ratio, tumor-to-blood ratio: 40.42 ± 1.59, 14.72 ± 2.77 at 4 h p.i., respectively), and the lowest estimated radiation absorbed dose, highlighting its potential as a clinical SPECT imaging probe for tumor PD-L1 detection. [ABSTRACT FROM AUTHOR]

Introduction: Prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of Prostate cancer (PCa). In this study, we introduce the freeze-dried kit formulation of [99mTc]Tc-HYNICALUG for easy clinical evaluation of prostate cancer. Methods: In this work, an in silico modeling of the urea-based PSMA small molecule (HYNIC-ALUG) was performed to check its interaction with human glutamate carboxypeptidase II and compared it with experimental results. The HYNIC-PSMA kit was formulated for easy preparation of [99mTc]Tc-HYNIC-ALUG. The kit contained a freeze-dried mixture of HYNIC-ALUG, coligands SnCl2.2H2O, and antioxidant D-mannitol. Results: The calculated Ki value (inhibition/dissociation constant) was 4.55 which showed excellent binding affinity of HYNIC-ALUG with PSMA. miLogP and cLogS values are -4.04 and -3.07 respectively showing its hydrophilic character and predicting its excellent distribution in biological fluids. Subsequently, the radiochemical purity of the HYNIC-PSMA kit was 99.1 ± 1.32% (n = 6) determined by radio-ITLC and by HPLC as well. In vitro stability in saline and serum was studied up to 4 h and showed high stability (≥ 96%). The distribution of [99mTc]Tc-HYNIC-ALUG was carried out in two patients and SPECT/CT planar images were acquired at 2h and 4h respectively. Bio-physiological distribution of [99mTc]Tc- HYNIC-ALUG was observed normally in lacrimal, salivary glands, liver, spleen, gut, kidneys, and urinary bladder. Conclusion: The HYNIC-ALUG freeze-dried kit could be used for easy preparation of [99mTc]Tc-HYNIC-ALUG and can be considered as a potential agent for the diagnosis, staging, and restaging of advanced prostate cancer. [ABSTRACT FROM AUTHOR]

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 "[99mTc]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 [99mTc]NaTcO4 for 10 min at room temperature to obtain [99mTc]Tc-(Ham-SCUE)2. [99mTc]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 [99mTc]Tc-(Ham-SCUE)2. The biodistribution of [99mTc]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: [99mTc]Tc-(Ham-SCUE)2 was acquired at radiochemical yields of 56% with a radiochemical purity of over 95%. The cellular uptake level of [99mTc]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). IC50 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 [99mTc]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: [99mTc]Tc-(Ham-SCUE)2 has the potential to be a SPECT imaging agent for diagnosing high PSMA-expressing prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Personalised multi-compartment dosimetry based on [99mTc]Tc-MAA is a valuable tool for planning 90Y radioembolization treatments. The establishment and effective application of dose–effect relationships in yttrium-90 (90Y) radioembolization requires [99mTc]Tc-MAA SPECT quantification ideally independent of clinical site. The purpose of this multi-centre phantom study was to evaluate inter-site variability of [99mTc]Tc-MAA imaging and evaluate a standardised imaging protocol. Data was obtained from the TARGET study, an international, retrospective multi-centre study including 14 sites across 8 countries. The impact of imaging related factors was estimated using a NEMA IQ phantom (representing the liver), and a uniformly filled cylindrical phantom (representing the lungs). Imaging was performed using site-specific protocols and a standardized protocol. In addition, the impact of implementing key image corrections (scatter and attenuation correction) in the site-specific protocols was investigated. Inter-site dosimetry accuracy was evaluated by comparing computed Lung Shunt Fraction (LSF) measured using planar imaging of the cylindrical and NEMA phantom, and contrast recovery coefficient (CRC) measured using SPECT imaging of the NEMA IQ phantom. Results Regarding the LSF, inter-site variation with planar site-specific protocols was minimal, as determined by comparing computed LSF between sites (interquartile range 9.6–10.1%). A standardised protocol did not improve variation (interquartile range 8.4–9.0%) but did improve mean accuracy compared to the site-specific protocols (5.0% error for standardised protocol vs 8.8% error for site-specific protocols). Regarding the CRC, inter-system variation was notable for site-specific SPECT protocols and could not be improved by the standardised protocol (CRC interquartile range for 37 mm sphere 0.5–0.7 and 0.6–0.8 respectively), however the standardised protocol did improve accuracy of sphere:background determination. Implementation of key image corrections did improve inter-site variation (CRC interquartile range for 37 mm sphere 0.6–0.7). Conclusion Eliminating sources of variability in image corrections between imaging protocols reduces inter-site variation in quantification. A standardised protocol was not able to improve consistency of LSF or CRC but was able to improve accuracy.

Background: Personalised multi-compartment dosimetry based on [99mTc]Tc-MAA is a valuable tool for planning 90Y radioembolization treatments. The establishment and effective application of dose–effect relationships in yttrium-90 (90Y) radioembolization requires [99mTc]Tc-MAA SPECT quantification ideally independent of clinical site. The purpose of this multi-centre phantom study was to evaluate inter-site variability of [99mTc]Tc-MAA imaging and evaluate a standardised imaging protocol. Data was obtained from the TARGET study, an international, retrospective multi-centre study including 14 sites across 8 countries. The impact of imaging related factors was estimated using a NEMA IQ phantom (representing the liver), and a uniformly filled cylindrical phantom (representing the lungs). Imaging was performed using site-specific protocols and a standardized protocol. In addition, the impact of implementing key image corrections (scatter and attenuation correction) in the site-specific protocols was investigated. Inter-site dosimetry accuracy was evaluated by comparing computed Lung Shunt Fraction (LSF) measured using planar imaging of the cylindrical and NEMA phantom, and contrast recovery coefficient (CRC) measured using SPECT imaging of the NEMA IQ phantom. Results: Regarding the LSF, inter-site variation with planar site-specific protocols was minimal, as determined by comparing computed LSF between sites (interquartile range 9.6–10.1%). A standardised protocol did not improve variation (interquartile range 8.4–9.0%) but did improve mean accuracy compared to the site-specific protocols (5.0% error for standardised protocol vs 8.8% error for site-specific protocols). Regarding the CRC, inter-system variation was notable for site-specific SPECT protocols and could not be improved by the standardised protocol (CRC interquartile range for 37 mm sphere 0.5–0.7 and 0.6–0.8 respectively), however the standardised protocol did improve accuracy of sphere:background determination. Implementation of key image corrections did improve inter-site variation (CRC interquartile range for 37 mm sphere 0.6–0.7). Conclusion: Eliminating sources of variability in image corrections between imaging protocols reduces inter-site variation in quantification. A standardised protocol was not able to improve consistency of LSF or CRC but was able to improve accuracy. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (AuNPs) radiolabeled with therapeutic and diagnostic radioisotopes have been broadly studied as a promising platform for early diagnosis and treatment of many diseases including cancer. Our main goal for this study was the comparison of the biodistribution profiles of four different concentrations of gold nanoconjugates radiolabeled with Technetium-99m (99mTc). More specifically, AuNPs with an average diameter of 2 nm were functionalized with a tridentate thiol ligand. Four different concentrations were radiolabeled with 99mTc-tricarbonyls with high radiolabeling yields (>85%) and were further purified, leading to radiochemical purity of >95%. In vitro stability of the radiolabeled nanoconstructs was examined in cysteine and histidine solutions as well as in human serum, exhibiting robust radiolabeling up to 24 h post-preparation. Moreover, in vitro cytotoxicity studies were carried out in 4T1 murine mammary cancer cells. In vivo tracking of the radiolabeled nanoconjugates at both concentrations was examined in normal mice in order to examine the effect of AuNPs' concentration on their in vivo kinetics. Our work demonstrates that varying concentrations of radiolabeled AuNPs lead to notably different biodistribution profiles. [ABSTRACT FROM AUTHOR]

Xanthomicrol (4′,5-dihydroxy-6,7,8-trimethoxyflavone) is the main active component of Dracocephalum kotschyi Boiss leaf extract. It has showed selective cytotoxic activity against some cancer cell lines and little effect on human fetal foreskin fibroblast cells used as nonmalignant control. This study aimed to develop 99mTc-labeled xanthomicrol and to evaluate its efficiency as a new tumor imaging agent. l,l-Ethylene dicysteine (EC) chelator was conjugated to xanthomicrol. EC-Xanthomicrol was labeled with technetium-99m by using tin chloride as a reducing agent and incubating at room temperature. Radiochemical purity and in vitro stability were analyzed by thin layer chromatography and high-performance liquid chromatography. In vitro cellular uptake and binding profile of radio-conjugate was determined on C6 glioma cells. In vivo bioevaluation and imaging studies of [99mTc]Tc-EC-Xanthomicrol were performed in C6 glioma tumor induced rat at different time points after injection of radio-conjugate. The high radiochemical yield (>95 %) was achieved for [99mTc]Tc-EC-Xanthomicrol which was stable up to 6 h. The radio-conjugate indicated high cell uptake (35.12 % at 2 h) which demonstrated to be specific. Tumor uptake was seen for [99mTc]Tc-EC-Xanthomicrol (1.23 ± 0.14 %ID/g) at 1 h post injection. Scintigraphy confirmed that tumors could be visualized clearly with [99mTc]Tc-EC-Xanthomicrol. The results indicated that [99mTc]Tc-EC-Xanthomicrol has potential to be considered as a new radiotracer in glioma tumor imaging. [ABSTRACT FROM AUTHOR]

Due to its small size and high affinity binding, the engineered scaffold protein ADAPT6 is a promising targeting probe for radionuclide imaging of human epidermal growth factor receptor type 2 (HER2). In a Phase I clinical trial, [99mTc]Tc-ADAPT6 demonstrated safety, tolerability and capacity to visualize HER2 expression in primary breast cancer. In this study, we aimed to select the optimal parameters for distinguishing between breast cancers with high and low expression of HER2 using [99mTc]Tc-ADAPT6 in a planned Phase II study. HER2 expression was evaluated in primary tumours and metastatic axillary lymph nodes (mALNs). SPECT/CT imaging of twenty treatment-naive breast cancer patients was performed 2 h after injection of [99mTc]Tc-ADAPT6. The imaging data were compared with the data concerning HER2 expression obtained by immunohistochemical evaluation of samples obtained by core biopsy. Maximum Standard Uptake Values (SUVmax) afforded the best performance for both primary tumours and mALNs (areas under the receiver operating characteristic curve (ROC AUC) of 1.0 and 0.97, respectively). Lesion-to-spleen ratios provided somewhat lower performance. However, the ROC AUCs were still over 0.90 for both primary tumours and mALNs. Thus, lesion-to-spleen ratios should be further evaluated to find if these could be applied to imaging using stand-alone SPECT cameras that do not permit SUV calculations. [ABSTRACT FROM AUTHOR]

Previously, we designed the EuK-based PSMA ligand BQ0413 with an maE3 chelator for labeling with technetium-99m. It showed efficient tumor targeting, but our preclinical data and preliminary clinical results indicated that the renal excretion levels need to be decreased. We hypothesized that this could be achieved by a decrease in the ligand's total negative charge, achieved by substituting negatively charged glutamate residues in the chelator with glycine. The purpose of this study was to evaluate the tumor targeting and biodistribution of two new PSMA inhibitors, BQ0411 and BQ0412, compared to BQ0413. Conjugates were radiolabeled with Tc-99m and characterized in vitro, using PC3-pip cells, and in vivo, using NMRI and PC3-pip tumor-bearing mice. [99mTc]Tc-BQ0411 and [99mTc]Tc-BQ0412 demonstrated PSMA-specific binding to PC3-pip cells with picomolar affinity. The biodistribution pattern for the new conjugates was characterized by rapid excretion. The tumor uptake for [99mTc]Tc-BQ0411 was 1.6-fold higher compared to [99mTc]Tc-BQ0412 and [99mTc]Tc-BQ0413. [99mTc]Tc-BQ0413 has demonstrated predominantly renal excretion, while the new conjugates underwent both renal and hepatobiliary excretion. In this study, we have demonstrated that in such small targeting ligands as PSMA-binding EuK-based pseudopeptides, the structural blocks that do not participate in binding could have a crucial role in tumor targeting and biodistribution. The presence of a glycine-based coupling linker in BQ0411 and BQ0413 seems to optimize biodistribution. In conclusion, the substitution of amino acids in the chelating sequence is a promising method to alter the biodistribution of [99mTc]Tc-labeled small-molecule PSMA inhibitors. Further improvement of the biodistribution properties of BQ0413 is needed. [ABSTRACT FROM AUTHOR]

Using a one-pot cyclo-condensation process under microwave irradiation, derivatives of curcumin have been created. Evaluation their anti-inflammatory efficacy showed that they had stronger properties than curcumin. Additionally, the most active derivative was radiolabeled with the diagnostic radioisotope technetium-99m and prepared with a high radiochemical yield (96.5 ± 0.09%) and in vitro stability of up to 6 h. The in-vivo study in inflamed mice showed that [99mTc]Tc-curcumin derivative accumulated with a high target to non-target ratio. The gathered information confirmed the efficacy of the [99mTc]Tc-curcumin derivative as a novel possible tracer for the identification and localization of inflammation. [ABSTRACT FROM AUTHOR]

Synaptic trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) is thought to cause excitotoxicity brain ischemia. However, given the current inability to quantify AMPARs density in live human brains, clinical translation has been limited. In this study, in vivo and in vitro experiments were conducted to evaluate the factors affecting omberacetam drug labeling with technetium-99m as a potential radiotracer of AMPARs in brain imaging. Healthy Swiss albino mice (adult male; n = 25; weight 25–30 g; age 10–14 weeks) underwent Shimadzu modeling, followed by a random intravenous injection of 99mTc-omberacetam (0.2 mL, 3.7 MBq), which was subsequently radiosynthesized in the brain-targeting AMPARs utilizing a single-photon emission computed tomography nuclear neuroimaging. Under optimal conditions, 99mTc-omberacetam with a highest radiochemical purity of 98.9% was obtained with an optimum binding (energy = − 82.3 kcal/mol) to brain AMPARs and was stable in human serum for > 24 h. A high brain uptake was noted within a time window of 15–60 min. At 5 min, this signal uptake was 8.9 ± 0.1% of the injected dose per gram (ID/g), crossing the blood–brain barrier and surpassing the uptake of commercially available brain perfusion imaging agents such as 125I-iododomperidone (5.6% ID/g at 5 min) in mice, 99mTc-HMPAO (2.25% ID/g at 2 min) in rats, and 99mTc-ECD (4.7% ID/g at 6 h) in humans. This study is the first to show the feasibility of 99mTc-omberacetam radiotracing for human brain imaging. This could be a novel diagnostic and therapeutic neuroprotective target for the hyperacute stage of ischemic stroke. [ABSTRACT FROM AUTHOR]

The radiolabeled iron oxide nanoparticles constitute an attractive choice to be used as dual-modality contrast agents (DMCAs) in nuclear medical diagnosis, due to their ability to combine the benefits of two imaging modalities, for instance single photon emission computed tomography (SPECT) with magnetic resonance imaging (MRI). Before the use of any DMCA, the investigation of its plasma extra- and on/intra cellular distribution in peripheral human blood is of paramount importance. Here, we focus on the in vitro investigation of the distribution of 99mTc-DPD-Fe3O4 DMCA in donated peripheral human blood (the ligand 2-3-dicarboxypropane-1-1-diphosphonic-acid is denoted as DPD). Initially, we described the experimental methods we performed for the radiosynthesis of the 99mTc-DPD-Fe3O4, the preparation of whole blood and blood plasma samples, and their incubation conditions with 99mTc-DPD-Fe3O4. More importantly, we employed a gamma-camera apparatus for the direct imaging of the 99mTc-DPD-Fe3O4-loaded whole blood and blood plasma samples when subjected to specialized centrifugation protocols. The direct comparison of the gamma-camera data obtained at the exact same samples before and after their centrifugation enabled us to clearly identify the distribution of the 99mTc-DPD-Fe3O4 in the two components, plasma and cells, of peripheral human blood. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra. SPECT imaging using technetium-99m [99mTc] labeled trodat is the choice of imaging to differentiate PD from its other forms like drug-induced PD. Aims and Objectives: The main objective of our study was to prepare in-house sterile formulation of [99mTc]Tc-trodat and use in clinics. Materials and Methods: The labeling of trodat was standardized using glucoheptonate sodium salt (GHA), stannous chloride dihydrate (in 0.05 N HCl), and ethylenediaminetetraacetic acid (Na-EDTA). The preparation was mixed and autoclaved at 15 psi for 15 min. The standardised formulation was stored at 4°C, -20°C and -80°C and labeling with 99mTc was tested for up to 6 days. The radiochemical purity, chemical impurities, and endotoxin levels were tested. The frozen formulation was tested in swiss mice (n = 3) for biodistribution studies at 4 h. Around 18 ± 2 mCi was injected intravenously in each patient (n = 5) and the image was acquired at 4 h post-injection. Results: The radiochemical purity of the preparation was 98.3 ± 1.4% with a retention time of 16.8 ± 1.5 min as compared to 4.0 ± 0.5 min for free 99mTc. Animal distribution showed highest uptake in liver and dual excretion via hepatobiliary and renal system. [99mTc]Tc-trodat imaging was able to differentiate both caudate and putamen. Conclusions: In-house frozen preparation was advantageous, as it has decreased the chance of manual error as compared to daily make up formulations and economical as compared to commercially available kits. [ABSTRACT FROM AUTHOR]

Abstract Background Despite the development of positron emission tomography (PET), single photon emission computed tomography (SPECT) still accounts for around 80% of all examinations performed in nuclear medicine departments. The search for new radiotracers or chelating agents for Technetium-99m is therefore still ongoing. O-TRENSOX and O-TRENOX two synthetic siderophores would be good candidates for this purpose as they are hexadentate ligands based on the very versatile and efficient 8-hydroxyquinoline chelating subunit. First, the radiolabeling of O-TRENOX and O-TRENSOX with 99mTc was investigated. Different parameters such as the quantity of chelating agent, type of reducing agent, pH and temperature of the reaction mixture were adjusted in order to find the best radiolabeling conditions. Then an assessment of the partition coefficient by measuring the distribution of each radiosynthesized complex between octanol and phosphate-buffered saline was realized. The complex’s charge was evaluated on three different celluloses (neutral, negatively charged P81 and positively charged DE81), and finally in vivo studies with biodistribution and SPECT imaging of [99mTc]Tc-O-TRENOX and [99mTc]Tc-O-TRENSOX were performed. Results The radiolabeling studies showed a rapid and efficient complexation of 99mTc with both chelating agents. Using tin pyrophosphate as the reducing agent and a minimum of 100 nmol of ligand, we obtained the [99mTc]Tc-O-TRENOX complex with a radiochemical purity of more than 98% and the [99mTc]Tc-O-TRENSOX complex with one above 97% at room temperature within 5 min. [99mTc]Tc-O-TRENOX complex was lipophilic and neutral, leading to a hepatobiliary elimination in mice. On the contrary, the [99mTc]Tc-O-TRENSOX complex was found to be hydrophilic and negatively charged. This was confirmed by a predominantly renal elimination in mice. Conclusions These encouraging results allow us to consider the O-TRENOX/99mTc and O-TRENSOX/99mTc complexes as serious candidates for SPECT imaging chelators. This study should be continued by conjugating these tris-oxine ligands to peptides or antibodies and comparing them with the other bifunctional agents used with Tc.

Scintigraphy and Positron Emission Tomography (PET) are both nuclear medicine imaging techniques, providing functional information of the imaged areas. Scintigraphy is a two-dimensional projected imaging technique that was introduced in equine imaging in the late 1970s. Scintigraphy allows imaging of large body parts and can cover multiple areas, remaining the only technique commonly used in horses for whole body imaging. PET is a cross-sectional imaging technique, first used in horses in 2015, allowing higher resolution three-dimensional functional imaging of the equine distal limb. This manuscript will cover current use and values of these two modalities in equine lameness diagnosis.

With the development of PD-1/PD-L1 immune checkpoint inhibitor therapy, the ability to monitor PD-L1 expression in the tumor microenvironment is important for guiding therapy. This study was performed to develop a novel radiotracer with optimal pharmacokinetic properties to reflect PD-L1 expression in vivo via single-photon emission computed tomography (SPECT) imaging. [99mTc]Tc-HYNIC-WL12-tricine/M (M = TPPTS, PDA, ISONIC, 4-PSA) complexes with high radiochemical purity (>97%) and suitable molar activity (from 100.5 GBq/μmol to 300 GBq/μmol) were prepared through a kit preparation process. All 99mTc-labeled HYNIC-WL12 radiotracers displayed good in vitro stability for 4 h. The affinity and specificity of the four radiotracers for PD-L1 were demonstrated both in vitro and in vivo. The results of biodistribution studies displayed that the pharmacokinetics of the 99mTc-HYNIC-conjugated radiotracers were significantly influenced by the coligands of the radiotracers. Among them, [99mTc]Tc-HYNIC-WL12-tricine/ISONIC exhibited the optimal pharmacokinetic properties (t1/2α = 8.55 min, t1/2β = 54.05 min), including the fastest clearance in nontarget tissues, highest tumor-to-background contrast (e.g., tumor-to-muscle ratio, tumor-to-blood ratio: 40.42 ± 1.59, 14.72 ± 2.77 at 4 h p.i., respectively), and the lowest estimated radiation absorbed dose, highlighting its potential as a clinical SPECT imaging probe for tumor PD-L1 detection.

Metallothioneins are a special group of low-molecular-weight proteins with metal-binding properties, which make them promising chelators for the development of targeted radiopharmaceuticals, as well as with technetium-99m. The aim of this work is to study the biodistribution of 99mTc-metallothionein conjugate (99mTc-MT) in intact mice in comparison with unbound technetium-99m (Na99mTcO4). Low uptake of 99mTc-MT in the thyroid gland (1.20 ± 0.30%/g versus 267.2 ± 59.0%/g for Na99mTcO4) demonstrates the high stability of 99mTc-MT in vivo. The 99mTc-MT complex is rapidly eliminated from the bloodstream through the kidneys and is characterized by a reduced uptake in most organs and tissues compared to Na99mTcO4. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA), which is overexpressed in advanced prostate cancer, is a well-established target for the development of antitumor diagnostic and therapeutic radiopharmaceuticals. The aim of this work is the preclinical study of the pharmacokinetics of a new radiopharmaceutical 99mTc-PSMA. Tumor uptake of 99mTc-PSMA is 1.81–3.91%/g with a maximum uptake of 3.91 ± 0.35%/g at 3 h of post-injection. The highest uptake (up to 140.11%/g) of 99mTc-PSMA throughout the study was observed in the kidneys. Tumor uptake of 99mTc-PSMA was higher than in other organs and tissues, except the kidneys [ABSTRACT FROM AUTHOR]

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 [99mTc]Tc-BQ0413. PSMA-transfected PC3-pip cells were used to evaluate the specificity and affinity of [99mTc]Tc-BQ0413 binding in vitro. PC3-pip tumor-bearing BALB/C nu/nu mice were used as an in vivo model. [99mTc]Tc-BQ0413 bound specifically to PC3-pip cells with an affinity of 33 ± 15 pM. In tumor-bearing mice, the tumor uptake of [99mTc]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 [99mTc]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, [99mTc]Tc-BQ0413 is a promising probe for the visualization of PSMA-positive lesions using single-photon emission computed tomography (SPECT). [ABSTRACT FROM AUTHOR]

Recent cancer therapies have focused on reducing immune suppression in the tumor microenvironment to prevent cancer progression and metastasis. PD-1 is a checkpoint protein that stops the immune response and is expressed on immune T cells. Cancer cells express a PD-1 ligand (PD-L1) to bind to the T-cell surface and activate immunosuppressive pathways. This study aimed to design, synthesize, and evaluate a 99mTc-labeled PD-L1-targeting cyclic peptide inhibitor (99mTc-iPD-L1) as a novel SPECT radiopharmaceutical for PD-L1 expression imaging. AutoDock software (version 1.5) was used to perform molecular docking for affinity calculations. The chemical synthesis was based on the coupling reaction of 6-hydrazinylpyridine-3-carboxylic acid with a 14-amino-acid cyclic peptide. iPD-L1 was prepared for 99mTc labeling. Radio-HPLC was used to verify radiochemical purity. The stability of the radiopeptide in human serum was evaluated by HPLC. iPD-L1 specificity was assessed by SDS-PAGE. [99mTc]Tc-iPD-L1 cellular uptake in PD-L1-positive cancer cells (HCC827 and HCT116) and biodistribution in mice with induced tumors were also performed. One patient with advanced plantar malignant melanoma received [99mTc]Tc-iPD-L1. The iPD-L1 ligand (AutoDock affinity: −6.7 kcal/mol), characterized by UPLC mass, FT-IR, and UV–Vis spectroscopy, was obtained with a chemical purity of 97%. The [99mTc]Tc-iPD-L1 was prepared with a radiochemical purity of >90%. In vitro and in vivo analyses demonstrated [99mTc]Tc-iPD-L1 stability (>90% at 24 h) in human serum, specific recognition for PD-L1, high uptake by the tumor (6.98 ± 0.89% ID/g at 1 h), and rapid hepatobiliary and kidney elimination. [99mTc]Tc-iPD-L1 successfully detected PD-L1-positive lesions in a patient with plantar malignant melanoma. The results obtained in this study warrant further dosimetric and clinical studies to determine the sensitivity and specificity of [99mTc]Tc-iPD-L1/SPECT for PD-L1 expression imaging. [ABSTRACT FROM AUTHOR]

Background: Despite the development of positron emission tomography (PET), single photon emission computed tomography (SPECT) still accounts for around 80% of all examinations performed in nuclear medicine departments. The search for new radiotracers or chelating agents for Technetium-99m is therefore still ongoing. O-TRENSOX and O-TRENOX two synthetic siderophores would be good candidates for this purpose as they are hexadentate ligands based on the very versatile and efficient 8-hydroxyquinoline chelating subunit. First, the radiolabeling of O-TRENOX and O-TRENSOX with 99mTc was investigated. Different parameters such as the quantity of chelating agent, type of reducing agent, pH and temperature of the reaction mixture were adjusted in order to find the best radiolabeling conditions. Then an assessment of the partition coefficient by measuring the distribution of each radiosynthesized complex between octanol and phosphate-buffered saline was realized. The complex's charge was evaluated on three different celluloses (neutral, negatively charged P81 and positively charged DE81), and finally in vivo studies with biodistribution and SPECT imaging of [99mTc]Tc-O-TRENOX and [99mTc]Tc-O-TRENSOX were performed. Results: The radiolabeling studies showed a rapid and efficient complexation of 99mTc with both chelating agents. Using tin pyrophosphate as the reducing agent and a minimum of 100 nmol of ligand, we obtained the [99mTc]Tc-O-TRENOX complex with a radiochemical purity of more than 98% and the [99mTc]Tc-O-TRENSOX complex with one above 97% at room temperature within 5 min. [99mTc]Tc-O-TRENOX complex was lipophilic and neutral, leading to a hepatobiliary elimination in mice. On the contrary, the [99mTc]Tc-O-TRENSOX complex was found to be hydrophilic and negatively charged. This was confirmed by a predominantly renal elimination in mice. Conclusions: These encouraging results allow us to consider the O-TRENOX/99mTc and O-TRENSOX/99mTc complexes as serious candidates for SPECT imaging chelators. This study should be continued by conjugating these tris-oxine ligands to peptides or antibodies and comparing them with the other bifunctional agents used with Tc. [ABSTRACT FROM AUTHOR]

To develop a low bladder accumulation SPECT prostate cancer imaging agent, 99mTc-P137 was prepared on the basis of 68Ga-P137 structure, and the probe was subjected to detailed preclinical evaluation and preliminary clinical translation studies. The labeled precursor HYNIC-P137 was prepared by solid-phase synthesis method, and the labeled precursor 99mTc was labeled with EDDA as co-ligand, and the product 99mTc-P137 was quality controlled. The lipid-water partition coefficient and in vitro stability of 99mTc-P137 were examined, and its uptake and inhibition on PSMA-positive and negative cells were investigated. Biodistribution in normal Kunming mice and SPECT/CT imaging in hormonal mice were performed, and finally, clinical translation studies were performed. The results showed that the precursor HYNIC-P137 could be easily obtained from solid-phase synthesis, and the labeled product 99mTc-P137 had a radiochemical purity close to 100%, good in vitro stability and high hydrophilicity. Normal Kunming mouse biodistribution showed rapid blood clearance of this probe, which was mainly metabolized by the kidney. MicroSPECT/CT of tumor-bearing mice showed that 99mTc-P137 was concentrated mainly in PSMA-positive tumors and renal regions, and both could be significantly inhibited, showing a high degree of intra-specific specificity. Clinical translation showed low accumulation of 99mTc-P137 in the bladder, high intrahepatic radioactivity, and good detection performance for prostate cancer foci in situ and lymph node metastases. It was shown that 99mTc-P137 with high affinity and low bladder accumulation is a novel ODAP-based SPECT prostate cancer imaging probe.

Gold nanoparticles (AuNPs) radiolabeled with therapeutic and diagnostic radioisotopes have been broadly studied as a promising platform for early diagnosis and treatment of many diseases including cancer. Our main goal for this study was the comparison of the biodistribution profiles of four different concentrations of gold nanoconjugates radiolabeled with Technetium-99m (99mTc). More specifically, AuNPs with an average diameter of 2 nm were functionalized with a tridentate thiol ligand. Four different concentrations were radiolabeled with 99mTc-tricarbonyls with high radiolabeling yields (>85%) and were further purified, leading to radiochemical purity of >95%. In vitro stability of the radiolabeled nanoconstructs was examined in cysteine and histidine solutions as well as in human serum, exhibiting robust radiolabeling up to 24 h post-preparation. Moreover, in vitro cytotoxicity studies were carried out in 4T1 murine mammary cancer cells. In vivo tracking of the radiolabeled nanoconjugates at both concentrations was examined in normal mice in order to examine the effect of AuNPs’ concentration on their in vivo kinetics. Our work demonstrates that varying concentrations of radiolabeled AuNPs lead to notably different biodistribution profiles.

In the present study, the aim is to synthesize and introduce the combination of methoxy amido xanthate MAX and then label it with 99mTc radionuclide as a novel diagnostic agent for single-photon computed tomography (SPECT) imaging. A chelator-designed ligand was synthesized from a blend of chloroacetamide and xanthate in certain proportions. After that MAX ligand labeling process was performed by directly milking 99mTc from the generator (99Mo / 99mTc). Thus, tin chloride was employed as a reducing agent, and the effect of parameters such as additives like ascorbic acid, changing the concentration of the cheating agent, and pH were evaluated to optimize the labeling conditions. The product was then identified by infrared spectroscopy (FTIR) and magnetic resonance imaging (NMR). Labeling of the complex at laboratory temperature was determined to be 93%. The new 99mTc-MAX radiopharmaceutical with a radionuclide and radiochemical purity of over 90% can be used as an encouraging diagnostic agent in clinics and preclinical studies, which will be addressed in future studies.

This study presents the synthesis and characterization of chitosan-glutamine-based biocompatible nanoparticles (nano-conjugate) as a platform for developing an efficient nano-radiopharmaceutical agent for liver imaging. The nanoparticles were labeled with technetium-99 m, resulting in the formation of 99mTc-chitosan-glutamine. Various characterization techniques, including furrier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H NMR) were performed for confirmation of synthesized nano-conjugate. Scanning electron microscopy (SEM), dynamic light scattering (DLS), and static light scattering (SLS) spectroscopies were employed to investigate the particle properties such as size, zeta potential, and molecular weight. MTT assay was conducted to study the toxicity of chitosan-glutamine showing that nano-conjugate had a toxicity on cancer cell in-vitro. In-vivo studies were conducted by administering 99mTc-chitosan-glutamine to mice, followed by whole body SPECT imaging. The imaging process was performed at three different time points post-injection: 15, 60, and 120 min. The SPECT results revealed a significantly accumulation in the liver. Also, biodistribution study showed that accumulation in liver (% ID/g = 23.15%) was significantly higher than other organs. Our in-vitro and in-vivo findings suggest that 99mTc-chitosan-glutamine could serve as a theranostic agent for cancer imaging using SPECT technology.

[99mTc] fonturacetam hydrazide was radiosynthesized to assess neuropsychiatric disorders by targeting the brain. The nootropic drug was labeled with technetium-99m, and factors affecting the labeling yield were studied. At optimum conditions, the radiocomplex was obtained at a high radiochemical yield (98.9%) and was stable in saline for up to 36 h and serum for more than 24 h. Labeled fonturacetam hydrazide was characterized and assessed in silico. Biodistribution studies in mice showed that the brain uptake of the complex was 8.8% injected dose per gram (% ID/g) at 5 min post-injection, surpassing the commercially available [99mTc] ECD (4.7% ID/g) and [99mTc] HMPAO (2.25% ID/g). All results suggested that the tracer is a good candidate to image the human brain for assessing neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

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The objective of this study was to develop radiolabeled ibuprofen (99mTc-ibu) for imaging and discrimination of inflammation and infection and compare its biodistribution in two different animal models. The development of radiolabeled ibuprofen as an imaging agent for inflammation and infection may have significant clinical implications for the diagnosis and management of various inflammatory and infectious diseases. This study provides a promising approach to the detection of sterile infections. Ibuprofen was radiolabeled with 99mTc using the stannous chloride method with a yield of 99.05 ± 0.83% (n = 5). The in vivo biological behavior of radiolabeled ibuprofen was determined in Wistar albino rat models of sterile inflammation and bacterial infection with Staphylococcus aureus gram-positive bacteria. Biodistribution studies were carried out at different time points, and the results were compared between the two animal models. The uptake of 99mTc-ibu in sterile inflammation sites at all time points was higher than that in the infection sites. This suggests that 99mTc-ibu can be used to discriminate between sterile inflammation and bacterial infection. The results of this study suggest that the detection of sterile infections with 99mTc-ibu is possible and highly encouraging. [ABSTRACT FROM AUTHOR]

The expression of prostate-specific membrane antigen (PSMA) is upregulated in prostate cancer (PCa) cells and PSMA-ligands have been radiolabeled and used as radiopharmaceuticals for targeted radionuclide therapy (TRT), single photon emission computed tomography (SPECT) or positron emission tomography (PET) molecular imaging, and radioguided surgery in PCa patients. Herein, we aimed at radiolabeling the PSMA-I&S cold kit with 99mTc, resulting in a radiopharmaceutical with high radiochemical yield (RCY) and stability for SPECT imaging and radioguided surgery in PCa malignancies. Various pre-clinical assays were conducted to evaluate the [99mTc]Tc-PSMA-I&S obtained by the cold kit. These assays included assessments of RCY, radiochemical stability in saline, lipophilicity, serum protein binding (SPB), affinity for LNCaP-PCa cells (binding and internalization studies), and ex vivo biodistribution profile in naive and LNCaP-PCa-bearing mice. The radiopharmaceutical was obtained with good RCY (92.05% ± 2.20%) and remained stable for 6 h. The lipophilicity was determined to be −2.41 ± 0.06, while the SPB was ∼97%. The binding percentages to LNCaP cells were 9.41% ± 0.57% (1 h) and 10.45% ± 0.45% (4 h), with 63.12 ± 0.93 (1 h) and 65.72% ± 1.28% (4 h) of the bound material being internalized. Blocking assays, employing an excess of unlabeled PSMA-I&S, resulted in a reduction in the binding percentage by 2.6 times. The ex vivo biodistribution profile confirmed high accumulation of [99mTc]Tc-PSMA-I&S in the tumor and the tumor-to-contralateral muscle ratio was ∼6.5. In conclusion, [99mTc]Tc-PSMA-I&S was successfully obtained by radiolabeling the cold kit using freshly eluted [99mTc]NaTcO4, exhibiting good RCY and radiochemical stability. The preclinical assays demonstrated that the radiopharmaceutical shows favorable characteristics for SPECT imaging and radioguided surgery in PCa patients.

Prostate-specific membrane antigen (PSMA) is a well-validated prostate cancer marker but reported PSMA-targeted tracers derived from the Lys-urea-Glu pharmacophore including the clinically validated [99mTc]Tc-EDDA/HYNIC-iPSMA have high off-target uptake in kidneys, spleen, and salivary glands. In this study, we synthesized and evaluated three novel 99mTc-labeled PSMA-targeted tracers and investigated if the tracers derived from the Lys-urea-Aad pharmacophore could have minimized uptake in off-target organs/tissues. In vitro competition binding assays showed that compared with HYNIC-iPSMA, the three novel ligands had slightly weaker PSMA binding affinity (average Ki = 3.11 vs. 8.96–11.6 nM). Imaging and ex vivo biodistribution studies in LNCaP tumor-bearing mice showed that [99mTc]Tc-EDDA/HYNIC-iPSMA and the three novel tracers successfully visualized LNCaP tumor xenografts in SPECT images and were excreted mainly via the renal pathway. The average tumor uptake at 1 h post-injection varied from 5.40 to 18.8%ID/g, and the tracers derived from the Lys-urea-Aad pharmacophore had much lower uptake in the spleen and salivary glands. Compared with the clinical tracer [99mTc]Tc-EDDA/HYNIC-iPSMA, the Lys-urea-Aad-derived [99mTc]Tc-EDDA-KL01127 had lower background uptake and superior tumor-to-background contrast ratios and is therefore promising for clinical translation to detect prostate cancer lesions with SPECT. [ABSTRACT FROM AUTHOR]

Low-energy electrons (Auger electrons) can be produced via the interaction of photons with gold atoms in gold nanorods (AuNRs). These electrons are similar to those emitted during the decay of technetium-99m (99mTc), a radioactive nuclide widely used for diagnostics in nuclear medicine. Auger and internal conversion (IC) electron emitters appropriately targeted to the DNA of tumors cells may, therefore, represent a new radiotherapeutic approach. 99mTc radiopharmaceuticals, which are used for diagnosis, could indeed be used in theragnostic fields when loaded on AuNRs and delivered to a tumor site. This work aims to provide a proof of concept (i) to evaluate AuNRs as carriers of 99mTc-based radiopharmaceuticals, and (ii) to evaluate the efficacy of Auger electrons emitted by photon-irradiated AuNRs in inducing radio-induced damage in T98G cells, thus mimicking the effect of Auger electrons emitted during the decay of 99mTc used in clinical settings. Data are presented on AuNRs' chemical characterization (with an aspect ratio of 3.2 and Surface Plasmon Resonance bands at 520 and 680 nm) and the loading of pharmaceuticals (after 99mTc decay) on their surface. Spectroscopic characterizations, such as UV-Vis and synchrotron radiation-induced X-ray photoelectron (SR-XPS) spectroscopies, were performed to investigate the drug–AuNR interaction. Finally, preliminary radiobiological data on cell killing with AuNRs are presented. [ABSTRACT FROM AUTHOR]

Abstract Background Radioguided surgery (RGS) has recently emerged as a valuable new tool in the management of recurrent prostate cancer (PCa). After preoperative injection of a 99mTc-labeled prostate-specific membrane antigen (PSMA) inhibitor, radioguided intraoperative identification and resection of lesions is facilitated by means of suitable γ-probes. First clinical experiences show the feasibility of RGS and suggest superiority over conventional lymph node dissection in recurrent PCa. However, commonly used [99mTc]Tc-PSMA-I&S exhibits slow whole-body clearance, thus hampering optimal tumor-to-background ratios (TBR) during surgery. We therefore aimed to develop novel 99mTc-labeled, PSMA-targeted radioligands with optimized pharmacokinetic profile to increase TBR at the time of surgery. Methods Three 99mTc-labeled N4-PSMA ligands were preclinically evaluated and compared to [99mTc]Tc-PSMA-I&S. PSMA affinity (IC50) and internalization were determined on LNCaP cells. Lipophilicity was assessed by means of the distribution coefficient logD 7.4 and an ultrafiltration method was used to determine binding to human plasma proteins. Biodistribution studies and static µSPECT/CT-imaging were performed at 6 h p.i. on LNCaP tumor-bearing CB17-SCID mice. Results The novel N4-PSMA tracers were readily labeled with [99mTc]TcO4 − with RCP > 95%. Comparable and high PSMA affinity was observed for all [99mTc]Tc-N4-PSMA-ligands. The ligands showed variable binding to human plasma and medium to low lipophilicity (logD 7.4 − 2.6 to − 3.4), both consistently decreased compared to [99mTc]Tc-PSMA-I&S. Biodistribution studies revealed comparable tumor uptake among all [99mTc]Tc-N4-PSMA-ligands and [99mTc]Tc-PSMA-I&S, while clearance from most organs was superior for the novel tracers. Accordingly, increased TBR were achieved. [99mTc]Tc-N4-PSMA-12 showed higher TBR than [99mTc]Tc-PSMA-I&S for blood and all evaluated tissue. In addition, a procedure suitable for routine clinical production of [99mTc]Tc-N4-PSMA-12 was established. Labeling with 553 ± 187 MBq was achieved with RCP of 98.5 ± 0.6% (n = 10). Conclusion High tumor accumulation and favorable clearance from blood and non-target tissue make [99mTc]Tc-N4-PSMA-12 an attractive tracer for RGS, possibly superior to currently established [99mTc]Tc-PSMA-I&S. Its GMP-production according to a method presented here and first clinical investigations with this novel radioligand is highly recommended.

Due to its small size and high affinity binding, the engineered scaffold protein ADAPT6 is a promising targeting probe for radionuclide imaging of human epidermal growth factor receptor type 2 (HER2). In a Phase I clinical trial, [99mTc]Tc-ADAPT6 demonstrated safety, tolerability and capacity to visualize HER2 expression in primary breast cancer. In this study, we aimed to select the optimal parameters for distinguishing between breast cancers with high and low expression of HER2 using [99mTc]Tc-ADAPT6 in a planned Phase II study. HER2 expression was evaluated in primary tumours and metastatic axillary lymph nodes (mALNs). SPECT/CT imaging of twenty treatment-naive breast cancer patients was performed 2 h after injection of [99mTc]Tc-ADAPT6. The imaging data were compared with the data concerning HER2 expression obtained by immunohistochemical evaluation of samples obtained by core biopsy. Maximum Standard Uptake Values (SUVmax) afforded the best performance for both primary tumours and mALNs (areas under the receiver operating characteristic curve (ROC AUC) of 1.0 and 0.97, respectively). Lesion-to-spleen ratios provided somewhat lower performance. However, the ROC AUCs were still over 0.90 for both primary tumours and mALNs. Thus, lesion-to-spleen ratios should be further evaluated to find if these could be applied to imaging using stand-alone SPECT cameras that do not permit SUV calculations.

Previously, we designed the EuK-based PSMA ligand BQ0413 with an maE3 chelator for labeling with technetium-99m. It showed efficient tumor targeting, but our preclinical data and preliminary clinical results indicated that the renal excretion levels need to be decreased. We hypothesized that this could be achieved by a decrease in the ligand’s total negative charge, achieved by substituting negatively charged glutamate residues in the chelator with glycine. The purpose of this study was to evaluate the tumor targeting and biodistribution of two new PSMA inhibitors, BQ0411 and BQ0412, compared to BQ0413. Conjugates were radiolabeled with Tc-99m and characterized in vitro, using PC3-pip cells, and in vivo, using NMRI and PC3-pip tumor-bearing mice. [99mTc]Tc-BQ0411 and [99mTc]Tc-BQ0412 demonstrated PSMA-specific binding to PC3-pip cells with picomolar affinity. The biodistribution pattern for the new conjugates was characterized by rapid excretion. The tumor uptake for [99mTc]Tc-BQ0411 was 1.6-fold higher compared to [99mTc]Tc-BQ0412 and [99mTc]Tc-BQ0413. [99mTc]Tc-BQ0413 has demonstrated predominantly renal excretion, while the new conjugates underwent both renal and hepatobiliary excretion. In this study, we have demonstrated that in such small targeting ligands as PSMA-binding EuK-based pseudopeptides, the structural blocks that do not participate in binding could have a crucial role in tumor targeting and biodistribution. The presence of a glycine-based coupling linker in BQ0411 and BQ0413 seems to optimize biodistribution. In conclusion, the substitution of amino acids in the chelating sequence is a promising method to alter the biodistribution of [99mTc]Tc-labeled small-molecule PSMA inhibitors. Further improvement of the biodistribution properties of BQ0413 is needed.

The radiolabeled iron oxide nanoparticles constitute an attractive choice to be used as dual-modality contrast agents (DMCAs) in nuclear medical diagnosis, due to their ability to combine the benefits of two imaging modalities, for instance single photon emission computed tomography (SPECT) with magnetic resonance imaging (MRI). Before the use of any DMCA, the investigation of its plasma extra- and on/intra cellular distribution in peripheral human blood is of paramount importance. Here, we focus on the in vitro investigation of the distribution of 99mTc-DPD-Fe3O4 DMCA in donated peripheral human blood (the ligand 2-3-dicarboxypropane-1-1-diphosphonic-acid is denoted as DPD). Initially, we described the experimental methods we performed for the radiosynthesis of the 99mTc-DPD-Fe3O4, the preparation of whole blood and blood plasma samples, and their incubation conditions with 99mTc-DPD-Fe3O4. More importantly, we employed a gamma-camera apparatus for the direct imaging of the 99mTc-DPD-Fe3O4-loaded whole blood and blood plasma samples when subjected to specialized centrifugation protocols. The direct comparison of the gamma-camera data obtained at the exact same samples before and after their centrifugation enabled us to clearly identify the distribution of the 99mTc-DPD-Fe3O4 in the two components, plasma and cells, of peripheral human blood.

Simple Summary: The receptor HER2 is overexpressed in some breast cancers. Tumours with a high HER2 expression can be successfully treated with the antibodies trastuzumab and pertuzumab. The radionuclide imaging of HER2 in disseminated cancer could help to select patients for treatment using these antibodies. Novel radiolabelled small-sized tracers, scaffold proteins, have shown excellent imaging properties in preclinical studies. The scaffold proteins [99mTc]Tc-ADAPT6 and DARPin [99mTc]Tc-(HE)3-G3 have been found to be safe in Phase I clinical trials. They showed promising results in the imaging of HER2. In this study, we compared the distribution of both tracers in the same patients with breast cancer to evaluate whether one of them has any decisive advantage. We found that both tracers provide an excellent visualization of tumours, but the accumulation of [99mTc]Tc-ADAPT6 in tumours is higher. The data from this study are essential for researchers developing imaging agents. Previous Phase I clinical evaluations of the radiolabelled scaffold proteins [99mTc]Tc-ADAPT6 and DARPin [99mTc]Tc-(HE)3-G3 in breast cancer patients have demonstrated their safety and indicated their capability to discriminate between HER2-positive and HER2-negative tumours. The objective of this study was to compare the imaging of HER2-positive tumours in the same patients using [99mTc]Tc-ADAPT6 and [99mTc]Tc-(HE)3-G3. Eleven treatment-naïve female patients (26–65 years) with HER2-positive primary and metastatic breast cancer were included in the study. Each patient was intravenously injected with [99mTc]Tc-ADAPT6, followed by an [99mTc]Tc-(HE)3-G3 injection 3–4 days later and chest SPECT/CT was performed. All primary tumours were clearly visualized using both tracers. The uptake of [99mTc]Tc-ADAPT6 in primary tumours (SUVmax = 4.7 ± 2.1) was significantly higher (p < 0.005) than the uptake of [99mTc]Tc-(HE)3-G3 (SUVmax = 3.5 ± 1.7). There was no significant difference in primary tumour-to-contralateral site values for [99mTc]Tc-ADAPT6 (15.2 ± 7.4) and [99mTc]Tc-(HE)3-G3 (19.6 ± 12.4). All known lymph node metastases were visualized using both tracers. The uptake of [99mTc]Tc-ADAPT6 in all extrahepatic soft tissue lesions was significantly (p < 0.0004) higher than the uptake of [99mTc]Tc-(HE)3-G3. In conclusion, [99mTc]Tc-ADAPT6 and [99mTc]Tc-(HE)3-G3 are suitable for the visualization of HER2-positive breast cancer. At the selected time points, [99mTc]Tc-ADAPT6 has a significantly higher uptake in soft tissue lesions, which might be an advantage for the visualization of small metastases. [ABSTRACT FROM AUTHOR]

Lead shielding materials are standard for radiation protection to limit exposure for patients and health care workers. However, lead is both heavy and highly toxic. The benefits of non-lead products are becoming and interesting because they offer the benefits of being cheaper, lighter and non-toxicity. This study has explored the radiation shielding efficacy of bismuth oxide (Bi2O3) loaded into the epoxy-resin for a Technetium-99m (99mTc) and Iodine-131 (131I) radiopharmaceutical container. Gamma ray attenuation parameters of the samples were investigated and compared with original lead shielding. The results showed that linear attenuation coefficient and percentage attenuation are increased with increasing filler loading. In contrast, the half-value layer values were decreased when more Bi2O3 was added. The 50 wt% Bi2O3 provided the best gamma ray attenuation efficacy with attenuations of 99.99% and 99.87% at gamma ray energy 140 and 364 keV, respectively. In comparison to lead, the 50 wt% Bi2O3 presented a slightly different attenuation of about 1.64%, while the heaviness was halved. Therefore, we hypothesize that Bi2O3 loaded into the epoxy-resin has gamma ray shielding potential for containing 99mTc and 131I radiopharmaceuticals while both reducing cost and weight. [ABSTRACT FROM AUTHOR]

Gastrin-releasing peptide receptors (GRPRs) are overexpressed in the majority of primary prostate tumors and in prostatic lymph node and bone metastases. Several GRPR antagonists were developed for SPECT and PET imaging of prostate cancer. We previously reported a preclinical evaluation of the GRPR antagonist [99mTc]Tc-maSSS-PEG2-RM26 (based on [D-Phe6, Sta13, Leu14-NH2]BBN(6-14)) which bound to GRPR with high affinity and had a favorable biodistribution profile in tumor-bearing animal models. In this study, we aimed to prepare and test kits for prospective use in an early-phase clinical study. The kits were prepared to allow for a one-pot single-step radiolabeling with technetium-99m pertechnetate. The kit vials were tested for sterility and labeling efficacy. The radiolabeled by using the kit GRPR antagonist was evaluated in vitro for binding specificity to GRPR on PC-3 cells (GRPR-positive). In vivo, the toxicity of the kit constituents was evaluated in rats. The labeling efficacy of the kits stored at 4 °C was monitored for 18 months. The biological properties of [99mTc]Tc-maSSS-PEG2-RM26, which were obtained after this period, were examined both in vitro and in vivo. The one-pot (gluconic acid, ethylenediaminetetraacetic acid, stannous chloride, and maSSS-PEG2-RM26) single-step radiolabeling with technetium-99m was successful with high radiochemical yields (>97%) and high molar activities (16–24 MBq/nmol). The radiolabeled peptide maintained its binding properties to GRPR. The kit constituents were sterile and non-toxic when tested in living subjects. In conclusion, the prepared kit is considered safe in animal models and can be further evaluated for use in clinics. [ABSTRACT FROM AUTHOR]

To develop novel tumor imaging agents with high tumor uptake and excellent tumor/non-target ratios, a glucose derivative containing cyclohexane (CNMCHDG) was synthesized and labeled with Tc-99m. [99mTc]Tc-CNMCHDG was prepared by a kit formulation that was straightforward to operate and fast. Without purification, [99mTc]Tc-CNMCHDG had a high radiochemical purity of over 95% and great in vitro stability and hydrophilicity (log P = −3.65 ± 0.10). In vitro cellular uptake studies showed that the uptake of [99mTc]Tc-CNMCHDG was significantly inhibited by pre-treatment with D-glucose and increased by pre-treatment with insulin. Preliminary cellular studies have demonstrated that the mechanism by which the complex enters into cells may be related to GLUTs. The results of biodistribution and SPECT imaging studies displayed high tumor uptake and good retention of [99mTc]Tc-CNMCHDG in A549 tumor-bearing mice (4.42 ± 0.36%ID/g at 120 min post-injection). Moreover, [99mTc]Tc-CNMCHDG exhibited excellent tumor-to-non-target ratios and a clean imaging background and is a potential candidate for clinical transformation. [ABSTRACT FROM AUTHOR]

Objectives: Early detection of bone cancer is critical for treating symptoms, minimizing pain, and increasing overall quality of life. It is critical to develop novel radiopharmaceuticals with high labeling efficiency and stability for the diagnosis of bone cancer. This research aims to design a novel radiopharmaceutical that may be used to diagnose bone cancer. Materials and Methods: In this study, ibandronate sodium (IBD), a bisphosphonate analog, was radiolabeled with technetium-99m [99mTc] and quality control tests on the newly developed radiopharmaceutical ([99mTc]Tc-IBD) were performed using radioactive thin layer chromatography. After that, the incorporation of [99mTc]Tc-IBD into hydroxyapatite (HA) crystals and a human bone osteosarcoma cell line (U2OS) was tested. Results: According to the results obtained, optimal radiolabeling procedure was obtained for [99mTc]Tc-IBD with 200 µg.mL-1 IBD, 20 µg stannous chloride, and 99mTc with 37 MBq radioactivity. The reaction mixture was adjusted to pH 5.5 and incubated at room temperature for 15 min. The radiochemical purity of [99mTc]Tc-IBD was found to be greater than 95% at room temperature for up to 6 h. Additionally, chromatography analysis showed >95% [99mTc]Tc-IBD complex formation with promising stability for up to 24 h in saline and up to 2 h in cell medium. The percentage binding of IBD to HA was 83.70 ± 3.67 and the logP of [99mTc]Tc-IBD was -1.1014. The radiolabeled complex exhibited a higher rate of cell incorporation to U2OS cells compared to Reduced/Hydrolyzed 99mTcO4- . Conclusion: The newly produced radiopharmaceutical is very promising according to the results of in vitro cell culture, HA binding, and quality studies, and will be a step forward for further studies in nuclear medicine for bone cancer diagnostics. [ABSTRACT FROM AUTHOR]