Radiopharmaceutical Kit Research Articles

THE MOLECULAR INTERACTION AND ADMET PREDICTION OF MODIFIED JPH203 AS A POTENTIAL RADIOPHARMACEUTICAL KIT FOR MOLECULAR IMAGING OF CANCER: AN IN SILICO RESEARCH

Objective: In this study, various types of pharmacokinetic modifying linkers and chelators are combined with JPH203 to obtain the best-docked molecule for prospective radiopharmaceutical kits.
 Methods: AutoDock 4.2.6 and AutoDockTools 1.5.6 programs was used to do the molecular docking simulation and ADMET prediction was done using VNN-ADMET to predict the pharmacokinetics and toxicity of the ligand.
 Results: The result of this study showed that JPH203-linker K-NOTA has the best affinity with a docking score of about-10.7 kcal/mol and shows hydrogen interaction with Tyr259, which acts as key residue of the active site.
 Conclusion: Based on the results, JPH203-linker K-NOTA has good potential as a radiopharmaceutical kit of cancer.

The Use of Carbon Quantum Dot as Alternative of Stannous Chloride Application in Radiopharmaceutical Kits

Even today, technetium-99m is a radionuclide choice for diagnostic in nuclear medicine. The unique chemical and physical properties of technetium-99m make it suitable as an available radionuclide in many centers. In this study, we examined the potential of CQD as a reducing agent in the MDP kit. Citric acid-derived CQD was synthesized and confirmed by FT-IR, TEM, UV-Vis, XPS, and surface analysis. No cytotoxicity was observed by the MTT assay. They were reducing properties of the CQD confirmed by fluorescence microscopy. The MDP kit is prepared by evaluating different parameters that affect the radiolabeling yield, including ligand, time, and CQD. The optimum amount of each parameter is obtained by Box–Behnken software. Finally, fluorescent spectroscopy, SPECT imaging, and biodistribution study showed that CQD reduces technetium-99m. Accumulation of radiotracer in the femur showed that CQD could be used in a radiopharmaceutical kit.

Feasibility and Evaluation of Automated Methods for Radiolabeling of Radiopharmaceutical Kits with Gallium-68.

Recent gallium-68 labeled peptides are of increasing interest in PET imaging in nuclear medicine. Somakit TOC® is a radiopharmaceutical kit registered in the European Union for the preparation of [68Ga]Ga-DOTA-TOC used for the diagnosis of neuroendocrine tumors. Development of a labeling process using a synthesizer is particularly interesting for the quality and reproducibility of the final product although only manual processes are described in the Summary of Product (SmPC) of the registered product. The aim of the present study was therefore to evaluate the feasibility and value of using an automated synthesizer for the preparation of [68Ga]Ga-DOTA-TOC according to the SmPC of the Somakit TOC®. Three methods of preparation were compared; each followed the SmPC of the Somakit TOC®. Over time, overheads, and overexposure were evaluated for each method. Mean±SD preparation time was 26.2±0.3 minutes for the manual method, 28±0.5 minutes for the semi-automated, and 40.3±0.2 minutes for the automated method. Overcost of the semi-automated method is 0.25€ per preparation for consumables and from 0.58€ to 0.92€ for personnel costs according to the operator (respectively, technician or pharmacist). For the automated method, overcost is 70€ for consumables and from 4.06€ to 6.44€ for personnel. For the manual method, extremity exposure was 0.425mSv for the right finger, and 0.350mSv for the left finger; for both the semi-automated and automated method extremity exposure were below the limit of quantification. The present study reports for the first time both the feasibility of using a [68Ga]- radiopharmaceutical kit with a synthesizer and the limits for the development of a fully automated process.

Utilization of Clean Room for Radiopharmaceutical Kits Production

The radiopharmaceutical kit production facilities usually use a clean room with an aseptic process. Therefore, it is very important to conduct research on clean room utilization for the production of radiopharmaceutical kits. The data was taken from radiopharmaceutical product that produced at Center for Radioisotope and Radiopharmaceutical Technology (PTRR), National Nuclear Energy Agency (BATAN) from 2015 to 2018. The results indicate the use of clean room depends on the drying duration of the radiopharmaceutical kit. Almost all radiopharmaceutical kits are dried for two days such as MIBI, MDP, Ethambutol, MAA, and Tetrofosmin kits. There are only two kits that are dried for one day, DTPA and EDTMP kits. The ratio of monitoring of drying temperatures during the drying process of DTPA kit (one day) and MDP kit (two days) shows that in 2015 the freeze dryer still showed maximum performance compared to the next three years. The optimal utilization of clean room is in 2015 as much as 100% while in 2016, 2017 and 2018 the average utilization of clean room is around 66%. The production process frequency is the lowest in June, followed by January and December due to the maintenance schedule. The longer the process of drying radiopharmaceutical kits, the longer the clean room facilities operate. The production process of radiopharmaceutical kits in 2015 is the most optimal.

Use of real-time electronic Silicon diode extremity dose detectors; towards optimising monitoring and radiopharmacy technique

Extremity radiation doses are typically monitored using ring dosimeters worn at the base of the palmar side of the index finger. This measurement does not represent the maximum extremity doses received; however, fingertip dose can be estimated by multiplying by a factor of 3, as recommended by ICRP. Indeed, the literature reports a considerable factor range, between 1.5 and 7 and, furthermore, there is debate as to whether the non-dominant or dominant index finger should be monitored. Ring dosimeters provide monthly dose information but do not provide shorter term data which may inform on radiopharmacy technique optimisation. Accordingly, using ED3 Si diode Hp(0.07) electronic dosimeters, this study sought to establish optimum ring dosimeter placement, operator specific maximum extremity dose correction factors and to examine radiopharmacy operator technique towards optimising extremity dose. Si diode detectors were attached to the index fingertips of radiopharmacy operators, recording real-time dosimetry data at 2 s intervals. After an initial session, an educational discussion was carried out, reviewing dosimetry data and identifying potential areas for technique improvement. A subsequent radiopharmacy session was then monitored. After educational sessions we demonstrated a 35% and 48% reduction, respectively, in dose per unit activity for bone radiopharmaceutical kit and injection preparation, which together accounted for 60% of extremity doses received. This work will discuss the technique optimisation employed. Further, simultaneous dose measurement of fingertip and base of non-dominant index finger, together with ring dosimeter data, allowed for more accurate estimation of the maximum extremity dose received for each operator.

Computational Study of Imidazolylporphyrin Derivatives as a Radiopharmaceutical Ligand for Melanoma.

Melanoma is the most aggressive type of skin cancer. Metastatic melanoma is extremely difficult to treat with current therapy methods such as surgery. On the other hand, it is a good opportunity to develop a radiopharmaceutical using a radionuclide such as Technetium (Tc) for diagnostic and Rhenium (Re) for therapeutic purposes. T3,4BCPP has been be used as a radioimaging agent for melanoma cancers experimentally. The aim of the present research was to design new imidazolylporphyrin derivatives with better selectivity and higher affinity than those of T3,4BCPP by molecular modeling. Eight types of Re- and Tc-labeled imidazolylporphyrins were docked to Fibroblast Growth Factor Receptor 1 (FGFR1, PDB ID: 5AM6) using AutoDock 4.2. FGFR1 was simulated by Molecular Dynamic (MD) simulation for 30 ns using NAMD 2.10 at 37 °C. The obtained conformations were then applied in a molecular docking simulation. Dovitinib (natural ligand of FGFR1), Re- and Tc-T3, 4BCPP were used as references. The MD simulation resulted in an RMSD of 3.8 Å. From all the studied imidazolylporphyrin derivatives, Tc-cD3, 4BCPMIP and Re-cD3, 4BCPIP had the best docking parameter. Tc-cD3, 4BCPMIP had a free binding energy of -4.06 kcal/mol, while that of Re-cD3, 4BCPIP was -4.35 kcal/mol. It is concluded that cD3,4BCPMIP and cD3,4BCPIP are two potential candidate ligands for a melanoma radiopharmaceutical kit.

Avaliação dos custos para realização de controles de qualidade de radiofármacos marcados com [99mTc]tecnécio em serviços de medicina nuclear no Brasil

OBJETIVO: Estabelecer os custos dos controles de qualidade para os radiofármacos marcados com [99mTc]tecnécio nos serviços de medicina nuclear do Brasil, em atenção às resoluções RDC nº 38/2008 e RDC nº 63/2009 editadas pela Agência Nacional de Vigilância Sanitária. MATERIAIS E MÉTODOS: Foram apurados preços de materiais de consumo, equipamentos e de mão-de-obra para a realização dos controles de qualidade. Os valores foram convertidos para unidades de volume, tempo e outras unidades cabíveis para a determinação do preço unitário. RESULTADOS: O investimento para aquisição de materiais de consumo e equipamentos foi estimado ser de R$ 35.500,00. O custo final para o controle de cada kit variou entre R$ 6,44 e R$ 7,80, dependendo do produto a ser analisado e do profissional selecionado para execução do procedimento. Esses valores podem representar de 0,5% a 10% do valor recebido pelas instituições pela realização dos exames. Na prática, o custo efetivo pode ser menor, uma vez que o produto de um kit pode ser utilizado em diversos pacientes. CONCLUSÃO: Em face do ganho de qualidade e segurança dos pacientes, concluímos que os custos da implantação do programa de controle de qualidade podem ser absorvidos no planejamento financeiro dos serviços de medicina nuclear.

Preparation and characterization of [99TcO] apcitide: a technetium labeled peptide.

[99mTcO] apcitide (99mTcO(P246)), the technetium complex of the 13 amino acid, apcitide, cyclo-(D-Tyr-Apc-Gly-Asp-Cys)-Gly-Gly-Cys(Acm)-Gly-Cys(Acm)-Gly-Gly-Cys-NH2, where Apc is L-[S-(3-aminopropyl)]cysteine (an arginine mimetic) and Acm is the acetamidomethyl protecting group, has high affinity and selectivity for the GPIIb/IIIa receptor that is expressed on the membrane surface of activated platelets and plays an integral role in platelet aggregation and thrombus formation. Bibapcitide, a 26 amino acid, bis-succinimidomethyl ether-linked dimer of the peptide apcitide has been formulated as a single-vial, lyophilized kit having the trade name AcuTect. When sterile, nonpyrogenic sodium pertechnetate (99mTcO4-) in 0.9% sodium chloride is added to the AcuTect radiopharmaceutical kit and the resulting kit is heated, [99mTcO] apcitide forms. This is the first radiopharmaceutical to target acute deep vein thrombosis (DVT) in the lower extremities. We report here the preparation, purification, and isolation of the 99Tc complex of apcitide and its characterization to determine the mode of binding of Tc to apcitide. [99TcO] apcitide was prepared, on the macroscopic level, by reaction of [99TcOCl4]- with apcitide, purified by preparative HPLC and isolated as a trifluoroacetate salt. [99TcO] apcitide can also be formed from the reaction of bibapcitide and 99TcO4- in the presence of Sn(II) and glucoheptonate at 80 degrees C, conditions that mimic the radiopharmaceutical kit preparation. FTIR data show a Tc=O stretch at 961.2 cm(-1), in the range observed for anionic [TcVO]3+ amide thiolate complexes. The mass spectral data is in agreement with the formula, [C51H73O20N17S5Tc]-, consistent with retention of Acm groups and the Tc binding in the Gly11-Gly12-Cys13 region of the peptide. Despite significant spectral overlap due to numerous similar amino acids, all protons of apcitide and [99TcO] apcitide were unambiguously assigned. The observation of two nonequivalent Acm groups and the observation of only 10 NH-CH cross-peaks in the TOCSY and COSY spectra of [99TcO] apcitide (NH-CH cross-peaks were absent for Gly11-Gly12-Cys13), compared to all 13 cross-peaks found in apcitide, provided compelling evidence to support the 99Tc binding to the terminal Gly11-Gly12-Cys13 region of apcitide.

Radio-LC-MS for the characterization of 99mTc-labeled bioconjugates.

This report describes the first example of using radio-LC-MS for determining the composition of (99m)Tc radiopharmaceuticals at the tracer level. The in-line radiometric detector is a useful addition to a standard LC-MS and provides direct correlation between the MS data and the radioactive species in a radiopharmaceutical kit. Complexes [(99m)Tc(HYNICtide)(tricine)(L)] (RP444, L = TPPTS; RP445, L = TPPDS; and RP446, L = TPPMS) were prepared using a decayed generator eluant. All the ternary ligand (99m)Tc complexes show the expected monoprotonated molecular ions, (M + 1)(+), and diprotonated molecular ions, (M + 2)(2+). The LC-MS spectral data support the proposed structure and are consistent with those obtained for their corresponding (99)Tc analogues. Ternary ligand complexes [(99m)Tc(HYNICtide)(tricine)(L)] (L = ISONIC-HE and ISONIC-Sorb) are neutral, and the molecular weights are also lower than that of RP444. Using a fresh generator eluant (24 h prior elution), only 1-2 mCi of (99m)Tc [(7 x 10(-)(12))-(1.5 x 10(-)(11)) mol of technetium complex] are required to obtain a reasonably clean mass spectrum. Radio-LC-MS is a quick and accurate analytical tool for characterization of (99m)Tc radiopharmaceuticals at the tracer level.

Cellular inactivation induced by a radiopharmaceutical kit: role of stannous chloride

Stannous chloride (SnCl 2) has been used in many sectors of human activities such as food manufacturing and in nuclear medicine to produce radiopharmaceuticals labeled with technetium-99m ( 99mTc). Due to its importance and genotoxic potentiality, we decided to evaluate the biological effect induced by a nuclear medicine kit, which includes SnCl 2, in association with glucoheptonic acid (GHA) which is employed for brain and renal scintigraphies. These studies were carried out with the Escherichia coli AB1157 strain and the deoxyribonucleic acid (DNA) plasmid pUC 9.1. The experiments, with different concentrations of SnCl 2 and GHA, show an inverse relationship between both agents. When the GHA concentration was increased, the cellular inactivation induced by SnCl 2 was reduced, as measured by the number of viable cells. Moreover, GHA protects the DNA molecule against the damage induced by SnCl 2.

Influence of technetium-99m-labeling conditions on physico-chemical and related biological properties of an acylated poly-galactosidic macrophage targeting agent for inflammation imaging

The potential of 99m-Tc-J001 for the investigation of inflammatory lesions via the targeting of recruited macrophages (Mφ) has already been documented in several experimental models and in human diseases. To achieve a functional imaging of inflammation via Mφ targeting, minimal labeled colloid content and high in vivo stability of 99mTc-J001 are essential. The actual specificity of such scintigraphy is closely dependent upon the radiolabeling of only the J001 molecules available for Mφ targeting. To develop an appropriate radiopharmaceutical kit, optimization of the labeling conditions was achieved from a series of pilot formulations that were evaluated for radiolabeling efficiency and both in vitro and in vivo 99mTc-J001 stability. Colloids were characterized using autocorrelation spectroscopy and multiangle laser-light scattering, radioactive colloid content of the formulations being deduced from biodistribution studies. This work has made possible the definition of a formulation exhibiting a radiolabeling yield >97.0%, associated with in vivo stability and minimal colloid formation, thus greatly enhancing the specificity of such macrophage scintigraphy.

A simple method for producing a technetium-99m-labeled liposome which is stable In Vivo

A new method for labeling preformed liposomes with technetium-99m ( 99mTc) has been developed which is simple to perform and stable in vivo. Previous 99mTc-liposome labels have had variable labeling efficiencies and stability. This method consistently achieves high labeling efficiencies (> 90%) with excellent stability. A commercially available radiopharmaceutical kit—hexamethylpropyleneamine oxime (HM-PAO)—is reconstituted with 99mTcO − 4 and then incubated with preformed liposomes that encapsulate glutathione. The incubation takes only 30 min at room temperature. Liposomes that co-encapsulate other proteins such as hemoglobin or albumin, in addition to glutathione, also label with high efficiency. Both in vitro and in vivo studies indicate good stability of this label. Rabbit images show significant spleen and liver uptake at 2 and 20 h after liposome infusion without visualization of thyroid, stomach or bladder activity. This labeling method can be used to study the biodistribution of a wide variety of liposome preparations that are being tested as novel drug delivery systems. This method of labeling liposomes with 99mTc may also have applications in diagnostic imaging.

Technetium-99m-diethyl-IDA instant kit: Labelling kinetics and biological properties

A formulation of stannous-diethyl-IDA freeze-dried kit, containing 50 mg diethyl-IDA and 0.4 mg hydrated stannous chloride, to be labelled with technetium has been developed for hepatobiliary scintigraphy. Gel chromatography column scanning technique has been applied for determination of technetium fractions in the preapration. The optimal pH value of the preparation with a high hepatobiliary specificity was found between 5.5 to 6.0. Effect of ligand to metal ratio on the stability of the prepared Sn-diethyl-IDA solution prior mixing with technetium has been investigated. The reaction conditions (initial pH) between the ligand and stannous ion affects the percent hydrolysis of the labelled compund, i.e. the formation rate of the complex. The organ distribution data of99mTc-diethyl-IDA in mice for 60 minutes post injection were satisfactory. The radiopharmaceutical exhibits rapid blood clearance, great hepatic clearance and very short hepatocyte transit time. Uptake of the radiopharmaceutical in various organs of mouse at 5 minute post injection showed that the greater part of the injected radioactivity has distributed between liver and intestine. However, about 12% and 60% of the injected dose has been found in liver and intestine respectively. The renal uptake of the HB agent in mice is relatively low and decreases with time to become about 0.3% at 60 minutes post injection. Blood clearance data of the radiopharmaceutical kit in rabbits showed that the HB agent is-rapidly cleared, since the initial decrease was very fast with a half-time of 1.5 minutes.

Characterization and use of a gamma radiation TLC scanner for radiochemical purity measurements of radiopharmaceutical kit preparations of99mTc(dmpe)2Cl 2 +

A simple, low cost TLC scanner system for the characterization of γ-emitting radiopharmaceuticals is described. The TLC γ scanner has a linear response range of ∼0.074 Mbq up to ≥2.94 Mbq. The accuracy and reproducibility of measurement is better than ±5% (relative). The utility of this TLC scanner system is demonstrated by application to the radioanalytical evaluation of99mTc(dmpe)2Cl 2 + preparations. A comparison with HPLC radioanalytical separations is made.

Filling vials aseptically while monitoring for bacterial contamination

An aseptic system for prefilling radiopharmaceutical kit vials or syringes is described. The system combines ultrafiltration with a method for monitoring for bacterial contamination. It could be used in any vial or syringe prefilling operation and is not restricted to radiopharmaceuticals.