Samarium-153 EDTMP for metastatic bone pain palliation: The impact of europium impurities

PurposeTo evaluate the impact on the radiation protection policies of the radiocontaminants in Samarium-153 ethylenediamine tetramethylene phosphonate (¹⁵³Sm-EDTMP).MethodsThe internal contamination of patients treated with ¹⁵³Sm-EDMTP for palliation of painful disseminated multiple bone metastases due to long-lived impurities was assessed by direct measurements. These measurements were coupled with dose-rate measurements close to their bodies and spectroscopic analysis of the residual activity in post-treatment radiopharmaceutical vials.ResultsWhole-body counting carried out in six patients showed a 30–81-kBq europium −152 plus europium-154 contamination. The 0.85 mean ¹⁵²Eu- to -¹⁵⁴Eu activity ratio obtained by direct counting was similar to that assessed by analysis of post-treatment residual activities in twelve radiopharmaceutical vials following radiopharmaceutical injection.ConclusionsThe long-lived radiocontaminants in the patient's bodies and the treatment wastes require modifications of the applicable radiation protection policies.     

Synthesis,physicochemical and biological evaluation of tacrine derivative labeled with technetium-99m and gallium-68 as a prospective diagnostic tool for early diagnosis of Alzheimer’s disease

Design, physicochemical and biological studies of novel radioconjugates for the early diagnosis of Alzheimer's disease, based on the newly synthesized tacrine derivatives were performed. Novel tacrine analogues were labeled with technetium-99m and gallium-68. For all obtained radioconjugates ([^99mTc]Tc-Hynic-(tricine)₂NH(CH₂)_ntacrine and [⁶⁸Ga]Ga-DOTA-NH(CH₂)₉tacrine, where n = 2–9 denotes the number of methylene groups CH₂) the studies of physicochemical properties (lipophilicity, stability in the presence of an excess of standard amino acids cysteine or histidine, human serum and in cerebrospinal fluid) were performed. For two selected radioconjugates [^99mTc]Tc-Hynic-(tricine)₂NH(CH₂)₉Tac and [⁶⁸Ga]Ga-DOTA-NH(CH₂)₉tacrine (characterized with the highest lipophilicity values) the biological tests (inhibition of cholinesterases action, molecular docking and biodistribution studies) have been performed. All novel radioconjugates showed high stability in biological solutions used. Both selected radioconjugates proved to be good inhibitors of cholinesterases and be able to cross the blood-brain barrier. Radioconjugates [^99mTc]Tc-Hynic-(tricine)₂NH(CH₂)₉tacrine and [⁶⁸Ga]Ga-DOTA-NH(CH₂)₉tacrine fulfil the conditions for application in nuclear medicine. Radiopharmaceutical [⁶⁸Ga]Ga-DOTA-NH(CH₂)₉tacrine, due to increased accuracy and improved sensitivity in PET imaging, may be better potential diagnostic tool for early diagnosis of Alzheimer’s disease.     

Investigations into some aryl substituted bis(thiosemicarbazones) and their copper complexes

The synthesis of three bis(thiosemicarbazone) compounds formed by the reaction of benzil with either thiosemicarbazide, 4-methyl-3-thiosemicarbazide or 4-phenyl-3-thiosemicarbazide are reported. The compounds were characterised by NMR spectroscopy, mass spectrometry and in the case of benzil bis(4-methyl-3-thiosemicarbazone) and benzil bis(4-phenyl-3-thiosemicarbazone) by X-ray crystallography. Attempts to purify benzil bis(thiosemicarbazone) and benzil bis (4-methyl-3-thiosemicarbazone) by recrystallisation resulted in the isolation of cyclised products that were characterised by X-ray crystallography. The 3 bis(thiosemicarbazone) compounds were used to synthesise both Cu(II) and Cu(I) complexes. The copper(II) complexes were formed by the reaction of the proligands with copper(II) acetate which gave neutral copper(II) complexes in which the thiosemicarbazone is doubly deprotonated, acting as a dianionic ligand. The copper(II)-benzil bis(4-phenyl-3-thiosemicarbazonato) complex was characterised by X-ray crystallography to show the copper in an essentially square planar N₂S₂ environment. The copper(I) complexes were synthesised by reacting the bis (thiosemicarbazone) ligands with [Cu(CH₃CN)₄]PF₆ to give cationic complexes. The copper(I)-benzil-bis(thiosemicarbazone) complex was characterised by X-ray crystallography which revealed that the complex was a dimeric dication. Each of the benzil bis(thiosemicarbazone) ligands act as a bidentate N,S donor to each copper(I) atom, forming an overall helical structure in which each copper atom is in a strongly distorted tetrahedral N₂S₂ environment. Electrochemical measurements show that the copper(II)-benzil bis(thiosemicarbazonato) complex undergoes a reversible reduction at biologically accessible potentials.     

Synthesis,in vitro and in vivo characterization of <Superscript>64</Superscript>Cu(I) complexes derived from hydrophilic tris(hydroxymethyl)phosphane and 1,3,5-triaza-7-phosphaadamantane ligands

Four novel ⁶⁴Cu complexes ([⁶⁴Cu(thp)₄]⁺ (1), [⁶⁴Cu(TPA)₄]⁺ (2), [HC(CO₂)(pz^Me2)₂ ⁶⁴Cu(thp)₂] (3) and [HC(CO₂)(tz)₂ ⁶⁴Cu(thp)₂] (4), [where thp is tris(hydroxymethyl)phosphine, TPA is 1,3,5-triaza-7-phosphaadamantane, pz^Me2 is 3,5-dimethylpyrazole and tz is 1,2,4-triazole] were successfully synthesized and characterized. The complexes were produced in high radiochemical purity and yield (more than 98%) without the need for further purification. Their logP values and serum stabilities were measured and in vitro behavior was observed in cultured EMT-6 cells. The logP values (± standard deviation) obtained were −2.26 ± 0.04 (1), 0.01 ± 0.01 (2), −1.24 ± 0.03 (3) and −2.06 ± 0.03 (4). Complex 3 demonstrated the highest serum stability, with approximately 33% of the complex still intact after 1-h incubation. Complex 2 showed a rapid cell-association with EMT-6 cells, with more than 8.5% association at 2 h. This association was significantly higher (P < 0.001) than for the other three compounds after a 2-h incubation (1, 1.21%; 3, 0.63%; 4, 2.75%). Biodistribution and small-animal positron emission tomography/computed tomography was undertaken with 1 in mice bearing EMT-6 tumors. EMT-6 tumor uptake was high at 1 h (7.71 ± 2.17 %ID/g) and decreased slowly over 24 h (4 h, 4.90 ± 0.78 %ID/g; 24 h, 3.74 ± 0.73 %ID/g). The PET/CT images show that the EMT-6 tumors can be visualized at all time points. In this proof-of-concept study, we have successfully synthesized and characterized a novel series of versatile water-soluble Cu(I) complexes containing monophosphine ligands. We also report the use of 1 as a building block for new radiopharmaceuticals, perhaps the first time such a method has been used in the production of copper radiopharmaceuticals.     

Capillary electrophoresis of technetium radiopharmaceuticals

Diagnostically used ^99mTc kit radiopharmaceuticals were analyzed using capillary zone electrophoresis with radioactivity detection: ^99mTc-bis(bis(2-ethyloxyethyl)phosphino)ethane (^99mTc-Myoview, ^99mTc-Tetrofosmin), ^99mTc-trans(1,2-bis(dehydro-2,2,5,5,-tetramethyl-3-furanone-4-methylene-amino)ethane)-tris(3-methoxy-1-propyl)phosphine) (^99mTc-Technescan Q12, ^99mTc-Furifosmin), ^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI), ^99mTc- , -ethylenecysteine diethylester dimer (^99mTc-ECD), ^99mTc-d,l-hexamethylene propyleneamine oxime (^99mTc-HMPAO), ^99mTc-diethylenetriaminepentaacetic acid (^99mTc-DTPA), ^99mTc-ethylene hepatobiliary iminodiacetic acid (^99mTc-EHIDA), ^99mTc- , -ethylenecysteine dimer (^99mTc-EC), ^99mTc-mercaptoacetylglycylglycylglycine (^99mTc-MAG₃), ^99mTc-dimercaptosuccinic acid (^99mTc-DMSA), ^99mTc-methylene diphosphonate (^99mTc-MDP) and ^99mNaTcO₄. A pressure-driven capillary zone electrophoresis was employed to detect small anions of high electrophoretic mobility and cations within one run. Effective ^99mTc complex charges could be determined by a neutral internal standard. All complexes showed the expected electrophoretic behaviours in view of their charges. Pure products were obtained for the majority of the studied complexes. In the case of ^99mTc-Q12, ^99mTc-EHIDA and ^99mTc-MDP, complex mixtures were detected. The high potential of CE for the analysis of ^99mTc radiopharmaceuticals could be shown.     

Preparation and bioevaluation of 99mTc-HYNIC-annexin B1 as a novel radioligand for apoptosis imaging

Annexin B1, a novel Ca²⁺-dependent PS-binding protein, has been shown to have a high affinity for PS exposed on the surface of apoptotic cells. To develop and bioevaluate an annexin B1 based PS-targeting radiotracer, annexin B1 was radiolabeled with ^99mTc using HYNIC as a bifunctional chelator. Binding assays with activated platelets and apoptotic SP2/0 cells were carried out to evaluate the in vitro biological activity of ^99mTc-HYNIC-annexin B1. Biodistribution of this radioligand was studied in normal mice. Dexamethasone-induced murine thymus apoptosis and fas-mediated murine liver apoptosis models were used to investigate the ability of radiolabeled annexin B1 to detect apoptosis in vivo. The labeling procedure yielded a compound with up to 98% radiochemical purity and good in vitro stability. The in vitro binding assays indicated that ^99mTc-HYNIC-annexin B1 retain its PS-binding activity. Biodistribution of the compound in mice showed that ^99mTc-HYNIC-annexin B1 is rapidly cleared from the blood and predominantly accumulates in the kidney. The marked increase in dexamethasone-treated murine thymus uptake and fas-mediated murine liver uptake correlated with histologic evidence of apoptosis. These data suggested that ^99mTc-HYNIC-annexin B1 retain its in vitro and in vivo biological activities. This radiotracer may therefore be useful as a novel radioligand for the noninvasive detecting of PS externalization associated with apoptosis.     

Multicellular dosimetric chain for molecular radiotherapy exemplified with dose simulations on 3D cell spheroids

PurposeAbsorbed radiation dose-response relationships are not clear in molecular radiotherapy (MRT). Here, we propose a voxel-based dose calculation system for multicellular dosimetry in MRT. We applied confocal microscope images of a spherical cell aggregate i.e. a spheroid, to examine the computation of dose distribution within a tissue from the distribution of radiopharmaceuticals.MethodsA confocal microscope Z-stack of a human hepatocellular carcinoma HepG2 spheroid was segmented using a support-vector machine algorithm and a watershed function. Heterogeneity in activity uptake was simulated by selecting a varying amount of the cell nuclei to contain ¹¹¹In, ¹²⁵I, or ¹⁷⁷Lu. Absorbed dose simulations were carried out using vxlPen, a software application based on the Monte Carlo code PENELOPE.ResultsWe developed a schema for radiopharmaceutical dosimetry. The schema utilizes a partially supervised segmentation method for cell-level image data together with a novel main program for voxel-based radiation dose simulations. We observed that for ¹⁷⁷Lu, radiation cross-fire enabled full dose coverage even if the radiopharmaceutical had accumulated to only 60% of the spheroid cells. This effect was not found with ¹¹¹In and ¹²⁵I. Using these Auger/internal conversion electron emitters seemed to guarantee that only the cells with a high enough activity uptake will accumulate a lethal amount of dose, while neighboring cells are spared.ConclusionsWe computed absorbed radiation dose distributions in a 3D-cultured cell spheroid with a novel multicellular dosimetric chain. Combined with pharmacological studies in different tissue models, our cell-level dosimetric calculation method can clarify dose-response relationships for radiopharmaceuticals used in MRT.     

Médicaments radiopharmaceutiques : du diagnostic au théranostique des tumeurs neuroendocrines

Neuroendocrine tumors (NET) are a heterogeneous group originating from endocrine cells, which have the ability to develop themselves on various organs. Most of NET are well differentiated and have the capacity to produce different hormones and biogenic amines. NETs usually appear sporadically and can also be associated with different syndromes (multiple endocrine neoplasia). For the majority of NETs, surgical resection is the treatment of choice requiring the precise location of the tumor before surgery as well as the determination of the stage, followed by monitoring the progression of the disease. In the diagnostic process, nuclear medicine with molecular imaging plays a fundamental role. The secretory functions of these tumors enable the use of molecular imaging by targeting specific metabolic pathways or receptors. In addition, nuclear medicine also plays an important role in the field of therapy by replacing in one radiopharmaceutical drugs, the imaging suited radionuclide by replacing with a radionuclide emitting radiation suitable for therapy, also called vectorized internal radiotherapy. The activity of nuclear medicine, which enables diagnosis and treatment to be carried out using the same structures specific to the molecular targets of neuroendocrine tumors, is fully integrated into the new theragnostic approach, and constitutes one of its main pillars. The objective of this work is to describe the molecular targets expressed by NETs and corresponding radiopharmaceuticals, validated for human use (diagnosis and therapy).