Abstract
[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.
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Introduction
The human brain is a complex organ. The detailed molecular and subcellular processes and neuronal cell interactions underlying central nervous system diseases such as psychiatric conditions and neurodegenerative disorders are poorly understood [1, 2]. Single-photon emission computed tomography (SPECT) has grown in importance as a clinical diagnostic and research modality over the last few decades [3, 4]. SPECT can considerably increase our understanding of the pathogenesis and treatment of neuropsychiatric disorders by involving real-time visualization, in vivo characterization, and qualification of sophisticated biological processes and specific pathways [1]. The appealing technology provides a helpful tool for drug development [5] and assessing biochemical processes [6].
Racetams molecules are neuroprotectant and metabolic enhancers based on the endogenous neuropeptide cycloprolylglycine [7]. They are mainly used as nootropic drugs to treat cognitive deficits. Although the exact mechanism of action of racetams is not fully comprehended [8], they are thought to produce their effect by primarily modulating the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors [9, 10]; the predominant excitatory neurotransmitter receptors mediating synaptic transmission in the brain. The AMPA receptors dysfunction is thought to underlie certain neuronal disorders, including depression, schizophrenia, epilepsy, and Alzheimer’s disease [11,12,13], and their synaptic trafficking is believed to underlie neuronal plasticity, including learning and memory [14, 15]. Recently, several tracers based on racetam molecules were developed for brain imaging [16,17,18,19,20,21,22,23].
Fonturacetam hydrazide is a synthetic psychostimulatory racetam molecule that is 30–60 more potent than piracetam and administered for a broader range of indications [10]. Radiolabeled fonturacetam hydrazide could provide a tool to visualize the living human brain. Thus, it could assist in further elucidating the molecular and circuit bases of neuronal diseases and help develop new diagnostic and therapeutic options. This study investigated fonturacetam hydrazide radiolabeling with the γ-emitter technetium 99m and preliminarily evaluated its potential use as a tracer for brain imaging.
Experimental
Materials
All chemicals and reagents utilized in this work were of the highest purity grade. Fonturacetam hydrazide, 2-(2-oxo-4-phenylpyrrolidin-1-yl) acetohydrazide, MW 233.27, was purchased from ChemScence, New Jersey, USA. Pertechnetate was eluted from a moly generator supplied by ELUTEC, Brussels, Belgium. Double-distilled nitrogen-purged water was used for dissolution and dilution. Swiss Albino mice (weighing 20–25 g) were used for biodistribution studies and obtained from the Animal House of Labeled Compounds Department, Egyptian Atomic Energy Authority. Elemental Analyzer Vario EL was used for elemental analysis. The 1H-NMR and 13C-NMR spectra were performed using a Bruker AMX 500 MHz spectrometer in CDCl3 (TMS internal standard). Agilent Technologies Triple quad mass spectrometer was used for the Mass spectrum, and the polarity was set in the electrospray ionization (ESI) positive mode.
Methods
Labeling of fonturacetam hydrazide
Stannous chloride dihydrate solution (150 µg, 0.2 mL) was added to fonturacetam hydrazide solution (25 µg, 0.5 mL) in phosphate buffer (pH 6, 0.1 M) maintained under positive nitrogen pressure in a sterile penicillin vial. After that, a freshly eluted pertechnetate solution (~ 350 MBq) from a Moly generator was added to this mixture and subsequently incubated at room temperature for 25 min. In order to determine the optimal labeling conditions, different combinations of factors affecting the labeling yield were studied using varying amounts of fonturacetam hydrazide (5–50 µg), Stannous chloride dihydrate (25–250 µg) at different pH values (2–11) for different reaction times (5–40 min).
Radiochemical purity analysis
The radiochemical purity of the [99mTc] fonturacetam hydrazide was ascertained using silica gel-impregnated thin-layer chromatography (SG-TLC). Two separate development systems (saline and ethanol: water: ammonium hydroxide [2:5:1]) were employed to determine the percentages of labeled complex, free pertechnetate, and colloids present [24]. Aliquots (5 μL) from the reaction mixture were spotted on two TLC strips (each of 14 × 1.5 cm2). The development was performed in tightly closed jars filled with nitrogen gas to keep the labeled spots from oxidization. Following the development, the two radiochromatograms were dried, cut into 1 cm pieces, and counted separately using a gamma-scintillation counter. The radiochemical purity was determined using the following equation:
HPLC analysis and purification
High-pressure liquid chromatography (HPLC) was carried out using a Shimadzu model, USA, equipped with LC-9A pumps, a Rheodyne injector, a UV spectrophotometer detector (SPD-6A, Shimadzu, USA), and a radioisotope detector (Bioscan Inc., USA). Chromatography was performed on an RP‐18 column (250 × 4.6 mm, 10 µm particle size) at a 2.0 mL/min flow rate. The sampling volume was 10 µL. Elution was carried out via mobile phase systems consisting of acetonitrile/water/acetic acid (20:80:0.1%, v/v), and UV detection was monitored at 280–290 nm. HPLC analysis was used to identify [99mTc] fonturacetam hydrazide and confirm that the radiolabeled fonturacetam hydrazide was consistent with nonradioactive rhenium-labeled fonturacetam hydrazide [25]. In this regard, an aliquot of the radiolabeled complex was co-injected with the rhenium analog. Then, the retention times of the peaks detected in the UV channel (280–290 nm) and the radiometric channel were compared.
Synthesis and characterization of nonradioactive rhenium analog
The synthesis of the analytical rhenium standard compound was performed under similar conditions using potassium perrhenate to determine the structure of [99mTc] fonturacetam hydrazide [26]. Briefly, in a sterile penicillin vial, 2.5 mg (10.7 µmol) of fonturacetam hydrazide was dissolved in 10 mL of phosphate buffer (pH 6) and then sonicated for 5 min for complete dissolution. 1.1 mg (3.9 µmol) of potassium perrhenate and 2.6 mg (11.4 µmol) of stannous chloride dihydrate were dissolved separately in the minimum amount of double-distilled nitrogen-purged water. Then, they were added to the reaction vial. The pH of the reaction medium was adjusted to pH 6, and the vial was incubated at 25 °C for 25 min. The product (Re-fonturacetam hydrazide) was purified and separated with high-performance liquid chromatography. Then, it was characterized using 1H-NMR and 13C-NMR. The ACD/NMR Processor V12 software was used for NMR data analysis and structure prediction based on correlation [27]. The 1H NMR (500 MHz, CDCl3) spectrum showed peaks at δ ppm: 2.66 (d, 2H), 2.89 (d, 2H), 3.11 (d, 2H), 3.21 (m, 2H), 3.26 (d, 2H), 3.66 (d, 2H), 3.76 (d, 2), 4.59 (s, 2H), 6.49 (s, 2H), 7.23–7.26 (m, 10H), 8.38 (s, 2H). The 13C NMR (500 MHz, CDCl3) spectrum of the complex showed peaks at δ ppm: 35.20 (C7, C24), 40.20 (C11, C28), 46.38 (C13, C30), 52.70 (C8, C25), 69.89 (C14, C31), 126.90 (C5, C22), 127.07 (C1, C3, C18, C20), 129.03 (C4, C6, C21, C23), 141.19 (C2, C19), 173.86 (C10, C27). Mass spectrum [m/z (relative abundance)]: 31 (0.28), 41 (0.38), 79 (0.91), 105 (0.26), 117 (0.99), 119 (0.21), 158 (0.65), 160 (0.62), 162 (0.6), 174 (0.17), 184 (0.19), 186 (0.42), 188 (0.67), 199 (0.26), 201 (0.28), 203 (0.5), 218 (1), 405 (0.24), 437 (0.16), 453 (0.98), 455 (0.48), 483 (0.35), 497 (0.21), 538 (0.31), 550 (0.18), 552 (0.35), 592 (0.26), 640 (0.36), 642 (0.43), 654 (0.32), 670 (0.24). The chemical identity of [99mTc] fonturacetam hydrazide has been ascertained by comparing their analytical RP-HPLC radiochromatograms with UV–vis traces of the corresponding rhenium congener.
In silico assessment
A docking study was performed using iGemdock ver2.1 software to evaluate the targeting ability of [99mTc] fonturacetam hydrazide to AMPA receptors [20]. The x-ray crystallographic structure of the target protein was imported from RSCB Protein Data Bank (PDB ID: 3KG2). ChemBio3D ultra software was used to design the structure of [99mTc] fonturacetam hydrazide and then to predict the geometry-optimized three-dimensional model of the complex via energy minimization using molecular mechanics [28]. The most appropriate binding pose of the tested labeled complex was studied within the receptor binding site using iGemdock [29]. The labeled complex was subjected to accurate docking by setting a population size of 800 with 80 generations and 1 solution. Then, the docked ligand pose that exhibited lower binding energy was selected, and its interactions with the protein residues were analyzed.
In vitro radiochemical stability
The stability of [99mTc] fonturacetam hydrazide was tested at ambient temperature for 48 h. The complex (1 mL) was mixed with saline (2 mL), and at 1, 2, 4, 6, 12, 24, and 48 h, samples (2 µL) in triplicates were withdrawn and assessed by the SG-TLC method [30]. The increase (in %) of free pertechnetate and colloids indicated the labeled complex dissociation. The stability was also evaluated in the presence of serum at 37 °C. 0.2 mL of the complex was mixed with 1.8 mL of human serum and incubated for 48 h. Aliquots (2 µL) were taken from the mixture at different time intervals, spotted on SG-TLC, and developed using saline and ethanol: water: Ammonium hydroxide [2:5:1], as mentioned before. Then the in vitro stability (in %) was calculated [31,32,33].
Determination of partition coefficient (P)
The partition coefficient is a measure of drug lipophilicity. The labeled complex partition coefficient (P) was determined using our previously reported method with slight modification [34]. Briefly, the freshly prepared [99mTc] fonturacetam hydrazide was mixed with equal volumes of n-octanol (organic layer) and phosphate buffer (pH 7.4, 0.025 M, aqueous layer) in a centrifuge tube. The mixture was vortexed for 5 min at room temperature and then subjected to centrifugation at 8,000 rpm for 10 min. Subsequently, samples (100 μL) from the organic and aqueous layers were transferred to other tubes and counted using a well-type gamma counter (Scalar Ratemeter SR7, Nuclear Enterprises Ltd., USA). The experiment was conducted in triplicate, and the partition coefficient value was expressed as Log P and calculated using the following equation:
Biodistribution and clearance studies
The in vivo experimental studies were approved by the Egyptian Atomic Energy Authority Animal Ethics Committee. The studies design and protocols followed the guidelines set out by the Labeled Compounds Department. Swiss Albino mice weighing 20–25 g were used. The mice (5 mice for each set of an experiment) were housed in metabolic cages with free access given to food and water for the required time. Mice were allowed to acclimate for one week before intravenous administration of [99mTc] fonturacetam hydrazide (0.2 mL, 3.7 MBq) via the tail vein. At required time intervals (5, 15, 30, 60, and 120 min) post-injection (p.i.), mice were anesthetized with ketamine, weighed, and dissected for tracer tissue distribution determination. Blood samples were collected using cardiac puncture. The main organs (liver, spleen, lungs, kidneys, stomach, heart, intestine, and brain) were isolated, washed twice using normal saline, weighed, and counted for radioactivity using a NaI (Tl) γ ray scintillation counter. The obtained results were expressed as the percentage uptake of injected dose per g tissue (% ID/g ± SD), and the tracer's elimination rate constant was calculated.
Blocking study
Different amounts of unlabeled fonturacetam hydrazide (0–1000 μg) were intravenously injected into Swiss Albino mice 10 min before radiotracer administration to block the brain AMPA receptors. The percent tracer uptake of the brain was determined at 5 min post-tracer injection (n = 5).
Statistical analysis
All collected data were expressed as mean ± SD. Statistical differences were assumed to be reproducible when P < 0.05 using the ANOVA test.
Results and discussion
Preparation, quality control, and characterization of [99mTc] fonturacetam hydrazide
The presence of electron-donating atoms such as oxygen and nitrogen in the fonturacetam hydrazide structure, shown in Fig. 1, enhances its labeling with the transition metal technetium-99m.
The chemical structure of fonturacetam hydrazide
A [99mTc] fonturacetam hydrazide complex with a radiochemical yield of 98.9 ± 1.1% was obtained at 25 min reaction time by mixing fonturacetam hydrazide (50 µg) with pertechnetate (~ 350 MBq) in the presence of stannous chloride dihydrate (150 µg, 150 µL) at pH 6.
The radiochemical purity of the labeled complex was checked by two chromatographic techniques (SG-TLC and HPLC). In thin-layer chromatography, the [99mTc] fonturacetam hydrazide and colloids (99mTcO2·nH2O) remained near the origin (Rf = 0–0.1) when normal saline was used as the mobile phase while the free pertechnetate (99mTcO4−) migrated with the solvent front (Rf = 0.8–1). However, using a mobile phase consisting of ethanol: water: Ammonium hydroxide [2:5:1], only the colloids (99mTcO2·nH2O) remained near the origin (Rf = 0–0.1), while the complex and the free pertechnetate moved with the solvent front (Rf = 0.8–1).
The HPLC radiochromatogram of the complex, depicted in Fig. 2, shows two different peaks at 1.2- and 11.2-min retention time corresponding to the free pertechnetate and the [99mTc] fonturacetam hydrazide complex, respectively. The unlabeled fonturacetam hydrazide peak can be detected on the UV channel at a retention time of 4.9 min. This result suggested the formation of a single labeled complex.
HPLC chromatogram of the [99mTc] fonturacetam hydrazide complex (a) and fonturacetam hydrazide (b). Comparative HPLC chromatogram of the radiotracer and corresponding rhenium complex (c)
Technetium and rhenium have remarkable chemical similarities due to their position in the Periodic Table. To elucidate the structure of the technetium labeled complex, its rhenium analog was synthesized and characterized. The NMR spectra were assessed and correlated to the structure using ACD/NMR Processor V12 software [29]. The structure of the [99mTc] fonturacetam hydrazide complex is shown in Fig. 3A. Chem Draw Ultra 11.0 was used to design the labeled complex structure and perform energy minimization. The software generated optimized geometries of three-dimensional structures of the [99mTc] fonturacetam hydrazide complex, and the values of the theoretically computed parameters are shown in Fig. 3B. The complex is expected to have an octahedral geometry with a ligand-to-metal ratio of 2:1.
A Chemical structure of the [99mTc] fonturacetam hydrazide complex. B Optimized three-dimensional structure of [99mTc] fonturacetam hydrazide
Labeling reaction optimization
The effects of various labeling reaction parameters such as ligand amount, reducing agent amount, pH of the reaction medium, and reaction time were studied and optimized in order to obtain the maximum radiochemical yield (RCY) of [99mTc] fonturacetam hydrazide. Experiments studying each factor were repeated in triplicate, and the results were expressed as mean ± SD.
Effect of ligand
The dependence of RCY on fonturacetam hydrazide concentration is depicted in Fig. 4A. The yield was low at a low fonturacetam hydrazide amount (46.1 ± 1.6% at 10 µg), with colloid formation (~ 12%) as a major impurity. The ligand concentration was insufficient to complex with all the reduced technetium converted to reduced hydrolyzed technetium colloid [35, 36]. The maximum RCY (98.9 ± 1.1%) was obtained by allowing the reaction to proceed at a ligand concentration of 50 µg. Any further increase in the amount of fonturacetam hydrazide has no significant effect on the RCY, which may be attributed to the fact that fonturacetam hydrazide solution containing 50 μg was enough to react with the entire generated reduced technetium-99m using stannous chloride as a reducing agent.
Effect of a fonturacetam hydrazide, b stannous chloride dihydrate, c pH, d pertechnetate, and e reaction time on the radiochemical yield of the [99mTc] fonturacetam hydrazide complex
Effect of reducing agent
Stannous chloride dihydrate is the most commonly used reducing agent to prepare technetium-99m radiopharmaceuticals. It reduces the pertechnetate ions (+7, source of radiolabel) eluted from the Moly generator to a more reactive lower oxidation state. As shown in Fig. 4B, the % RCY depended on the reducing agent amount present in the reaction medium. At low stannous content (25 µg), the % RCY was low (42.8 ± 0.7%), indicating that the stannous was insufficient to reduce all pertechnetate ions. The yield gradually increased by increasing the SnCl2·2H2O amount till reaching the most effective concentration (150 µg), giving 98.9 ± 1.1% RCY. Further increasing the reducing agent concentration, the RCY decreased gradually due to the formation of undesirable hydrolyzed oxidized tin colloids [37,38,39].
Effect of pH
The reaction pH is a crucial factor that needs to be controlled since it affects the labeling process and may affect the stability of the labeled complex. The optimum radiochemical conversion is significantly changed by changing pH from highly acidic to highly basic (Fig. 4C). pH 6 proved optimal, which may partly reflect the stability of the [99mTc] fonturacetam hydrazide complex (98.9 ± 1.1%). At pH 2, the % RCY was relatively low (51.1 ± 1.2%), with the appearance of free pertechnetate as the predominant species (32.8 ± 1.8%). Increasing the pH above the optimum value reduced the RCY to 82.6 ± 1.8 and 75.2 ± 0.4% at pH 9 and 11, respectively, with the formation of stannous hydroxide colloid as the predominant species [40].
Effect of radiometal
Variable amounts of pertechnetate activity (100–1500 MBq) were used to determine the optimal radioactive concentration during reconstitution, assess the stability of the complex in the presence of an excess amount of pertechnetate, and assess the feasibility of using the same vial for multiple patients to reduce imaging costs. As shown in Fig. 4D, the study's findings suggested 700 MBq was the best dosage. It was further demonstrated that activity in the range of 300–900 MBq might be employed, with the complex being stable against radiolysis.
Reaction time
Figure 4E illustrates the effect of reaction time on the RCY of the [99mTc] fonturacetam hydrazide complex. The reaction proceeded well at room temperature. The RCY reached 76 ± 1.8% within 10 min and increased with time till reaching its maximum value (98.9 ± 1.1%) at 25 min. After that, the RCY remained unchanged for more than 1 h [41].
Physicochemical evaluation
Stability
The shelf life of [99mTc] fonturacetam hydrazide was investigated to evaluate the time post-reconstitution during which the labeled drug remains suitable for human use. The results plotted in Fig. 5 indicated that the technetium-99 m labeled fonturacetam hydrazide remained stable at ambient temperature for up to 40 h without detecting significant side products that could lead to tracer accumulation in non-target organs or interfere with the imaging process.
In vitro stability of the [99mTc] fonturacetam hydrazide complex up to 48 h in saline at 25 °C and serum at 37 °C
The labeled complex in vitro stability was also evaluated at 37 °C in the presence of serum. The complex showed a stable profile for up to 24 h indicating suitability for human administration during this period. After that, the radiochemical purity decreased to 77.7 ± 0.9% within 48 h, probably due to interaction with serum constituents.
Partition coefficient
The partition coefficient is an important criterion used in assessing a candidate drug. It strongly influences drug pharmacokinetics, such as absorption, distribution within the body, and how rapidly it is metabolized and excreted. It also controls the pharmacological effect by influencing the ease with which a medication reaches its intended target within the body and the binding strength to the targeted receptor. The blood–brain-barrier (BBB) penetration is optimal for drugs targeting the brain when the partition coefficient value is 1.5–2.7. [99mTc] fonturacetam hydrazide experimentally determined log P was found to be 2.52 ± 0.2. That indicated the tracer lipophilicity and its ability to cross BBB.
In silico assessment
To evaluate the tracer binding to the target site, iGemdock 2.1 software was used. This software creates Van der Waal's, Hydrogen-Bonding and Electrostatic interaction profiles between receptors and ligands. After that, it reads the target coordinates of the protein and ligand molecule atoms sequentially and analyses their molecular interactions using flexible docking interactions. The binding energy to the protein active site is then calculated to analyze the interactions between the protein and the ligands. As shown in Fig. 6, the suggested interactions included hydrogen bonding and Van der Waal's interaction between the complex and the key amino acids (ASN344, GLN337, VAL338, and GLU339). The computer modeling revealed that the labeled complex has an optimal fit (Energy = − 102.05 kcal/mole) to the ligand binding site of the target protein [19, 20].
Docking pose and interactions profile of [99mTc] fonturacetam hydrazide to AMPA receptor
Biodistribution and clearance studies
All biological experiments were performed according to guidelines established by the Egyptian Atomic Energy Authority Animal Ethics Committee (ethical approval EAEA/2022/188). The in vivo uptake of the [99mTc] fonturacetam hydrazide in various body organs/tissues of Swiss Albino mice was studied. Data were collected, expressed as the mean of 5 experiments ± SD, and the results are presented in Table 1. The results showed a rapid distribution profile of the tracer throughout the body. The blood activity was initially high (22.3 ± 0.5% ID/g at 5 min post-injection (p.i.)) but decreased slowly to (6.2 ± 0.2% ID/g) within 120 min p.i. probably due to plasma protein binding. Fonturacetam hydrazide is metabolized by the liver, which interpreted the relatively high liver uptake of radioactivity (10.4 ± 0.7% ID/g at 30 min p.i.). The kidneys are the main excretion route of the labeled drug; consequently, the radioactivity in the kidneys increased with time till it reached 15.8 ± 0.2% ID/g and remained high with time compared to other organs. The radioactivity counted in the remaining organs was within the normal ranges. [99mTc] fonturacetam hydrazide highly accumulated in the brain at 5 min p.i. (8.8 ± 0.1% ID/g). Thereafter, the radioactivity slightly decreased to 7.4 ± 0.2, 5.7 ± 0.2, 4.5 ± 0.1, and 2.4 ± 0.1% ID/g at 15, 30, 60 and 120 min p.i. Interestingly, the maximum brain uptake of the tracer at 5 min (5.6 ± 0.2) was higher than currently used brain imaging radiopharmaceuticals for such as [99mTc] ECD and [99mTc] HMPAO (4.7 and 2.25%, respectively) [42]. The brain/blood ratio results indicated that the optimum time for using [99mTc] fonturacetam hydrazide as a radiotracer for brain imaging was 15–60 min. The Brain uptake and brain-to-blood ratio of several labeled racetams in mice at 5 min post-injection are outlined in Table 2.
Results of the clearance study, depicted in Fig. 7, revealed that the tracer followed first-order elimination kinetics, where a constant percentage of the drug is removed per unit of time. The elimination rate constant was computed and found to be 0.63 h−1.
Blood clearance of [99mTc] fonturacetam hydrazide in Swiss Albino mice
Blocking study
Different amounts of unlabeled fonturacetam hydrazide (0–1000 μg) were used to pre-dose the mice before the tracer injection. Following pre-dosing, the brain uptake of [99mTc] fonturacetam hydrazide at 5 min p.i. was determined, and results are shown in Fig. 8. It was observed that the tracer uptake by the brain was blocked by the non-labeled fonturacetam hydrazide in a dose-dependent manner, suggesting that its accumulation reflects interaction with the protein target. The results suggested that the tracer can be used for brain imaging.
Inhibition of [99mTc] fonturacetam hydrazide brain uptake in normal Swiss Albino at 5 min post-injection following pre-dosing with different amounts of unlabeled fonturacetam hydrazide
Conclusion
Fonturacetam hydrazide is a nootropic drug used to treat and manage cognitive deficits. Technetium-labeled fonturacetam hydrazide could provide a means to better understand the underlying mechanisms of physiology and pathology of neuropsychiatric disorders. This study investigated factors affecting the labeling yield of fonturacetam hydrazide with technetium-99m. Then the suitability of the labeled fonturacetam hydrazide as a radiotracer for brain imaging was assessed. All obtained results suggested the feasibility of the radiotracer. We recommend the [99mTc]technetium fonturacetam hydrazide for further assessment in different models of neuropsychiatric disorders.
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El-Kawy, O.A., Shweeta, H.A. & Sallam, K.M. Radiolabeling and evaluation of fonturacetam hydrazide as a radiotracer for visualization of brain function. J Radioanal Nucl Chem 332, 3273–3283 (2023). https://doi.org/10.1007/s10967-023-08966-6
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DOI: https://doi.org/10.1007/s10967-023-08966-6