Current Radiopharmaceuticals - Volume 12, Issue 1, 2019

Background and Objective: Although accounting for a relatively small proportion of all lung cancers, small cell lung cancer (SCLC) remains to be a global health concern with grim prognosis. Radiotherapy (RT) plays a central role in SCLC management either as a curative or palliative therapeutic strategy. There has been considerable progress in RT of SCLC, thanks to improved imaging techniques leading to accurate target localization for precise delivery of RT. Positron emission tomography (PET) is increasingly used in oncology practice as a non-invasive molecular imaging modality. Methods: Herein, we review the utility of molecular imaging with 2-deoxy-2-[fluorine-18] fluoro-Dglucose PET (18F-FDG PET) for SCLC from a radiation oncology perspective. Results: There has been extensive research on the utility of PET for SCLC in terms of improved staging, restaging, treatment designation, patient selection for curative/palliative intent, target localization, response assessment, detection of residual/recurrent disease, and prediction of treatment outcomes. Conclusion: PET provides useful functional information as a non-invasive molecular imaging modality and may be exploited to improve the management of patients with SCLC. Incorporation of PET/CT in staging of patients with SCLC may aid in optimal treatment allocation for an improved therapeutic ratio. From a radiation oncology perspective, combination of functional and anatomical data provided by integrated PET/CT improves discrimination between atelectasis and tumor, and assists in the designation of RT portals with its high accuracy to detect intrathoracic tumor and nodal disease. Utility of molecular imaging for SCLC should be further investigated in prospective randomized trials to acquire a higher level of evidence for future potential applications of PET.

Objective: Neuroendocrine Neoplasms (NENs) are generally defined as rare and heterogeneous tumors. The gastrointestinal system is the most frequent site of NENs localization, however they can be found in other anatomical regions, such as pancreas, lungs, ovaries, thyroid, pituitary, and adrenal glands. Neuroendocrine neoplasms have significant clinical manifestations depending on the production of active peptide. Methods: Imaging modalities play a fundamental role in initial diagnosis as well as in staging and treatment monitoring of NENs, in particular they vastly enhance the understanding of the physiopathology and diagnosis of NENs through the use of somatostatin analogue tracers labeled with appropriate radioisotopes. Additionally, the use of somatostatin analogues provides the ability to in-vivo measure the expression of somatostatin receptors on NEN cells, a process that might have important therapeutic implications. Results: A large body of evidences showed improved accuracy of molecular imaging based on PET/CT radiotracer with SST analogues (e.g. [68Ga]-DOTA peptide) for the detection of NEN lesions in comparison to morphological imaging modalities. So far, the role of imaging technologies in assessing treatment response is still under debate. Conclusion: This review offers the systems of classification and grading of NENs and summarizes the more useful recommendations based on data recently published for the management of patients with NENs, with special focus on the role of imaging modalities based on SST targeting with PET / CT radiotracers.

Background: Heart injury is one of the most important concerns after exposure to a high dose of radiation in chest cancer radiotherapy or whole body exposure to a radiation disaster. Studies have proposed that increased level of inflammatory and pro-fibrotic cytokines following radiotherapy or radiation events play a key role in the development of several side effects such as cardiovascular disorders. In the current study, we aimed to evaluate the expression of IL-4 and IL-13 cytokines as well as signaling pathways such as IL4Ra1, IL13Ra2, Duox1 and Duox2. In addition, we detected the possible protective effect of curcumin on the expression of these factors and infiltration of inflammatory cells. Materials and Methods: Twenty rats were divided into 4 groups including control; curcumin treated; radiation; and radiation plus curcumin. After 10 weeks, rats were sacrificed for evaluation of mentioned parameters. Results: Results showed an increase in the level of IL-4 and all evaluated genes, as well as increased infiltration of lymphocytes and macrophages. Treatment with curcumin could attenuate these changes. Conclusion: Curcumin could reduce radiation-induced heart injury markers in rats.

Objective: The characterization of cancerous tissue and bone metastasis can be distinguished by accurate assessment of accumulated uptake and activity from different radioisotopes. The various parameters and phenomena such as calibration factor, Compton scattering, attenuation and penetration intrinsicallyinfluence calibration equation, and the qualification of images as well. Methods: The camera calibration factor (CF) translates reconstructed count map into absolute activity map, which is determined by both planar and tomographic scans using different phantom geometries. In this study, the CF for radionuclides of Tc-99m and Sm-153 in soft tissue and bone was simulated by the Monte Carlo method, and experimental results were obtained in equivalent tissue and bone phantoms. It may be employed for the simultaneous correction of the scattering and attenuation rays interacted with the camera, leading to corrected counts. Also, the target depth (d) may be estimated by a combination of scattering and photoelectric functions, which we have published before. Results: The calibrated equations for soft tissue phantom for the radionuclides were obtained by RTc = - 10d+ 300 and RSm = -8d + 100, and the relative errors between the simulated and experimental results were 4.5% and 3.1%, respectively. The equations for bone phantom were RTc = -30d + 300 and RSm = - 10d + 100, and the relative errors were 5.4% and 5.6%. The R and d are in terms of cpm/mCi and cm. Besides, the collimators' impact was evaluated on the camera response, and the relevant equations were obtained by the Monte Carlo method. The calibrated equations as a function of various radiation angles on the center of camera's cells without using collimator indicated that both sources have the same quadratic coefficient by -2E-08 and same vertical width from the origin by 8E-05. Conclusion: The presented procedure may help determine the absorbed dose in the target and likewise optimize treatment planning.

Background: The SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]SRF101) is a Sulforhodamine 101 derivative that was previously synthesised by our group. The fluorescent dye SR101 has been reported as a marker of astroglia in the neocortex of rodents in vivo. Objective: The aim of this study was to perform a toxicological evaluation of [18F]SRF101 and to estimate human radiation dosimetry based on preclinical studies. Methods: Radiation dosimetry studies were conducted based on biokinetic data obtained from a mouse model. A single-dose toxicity study was carried out. The toxicological limit chosen was <100 μg, and allometric scaling with a safety factor of 100 for unlabelled SRF101 was selected. Results: The absorbed and effective dose estimated using OLINDA/EXM V2.0 for male and female dosimetric models presented the same tendency. The highest total absorbed dose values were for different sections of the intestines. The mean effective dose was 4.03 x10-3 mSv/MBq and 5.08 x10-3 mSv/MBq for the male and female dosimetric models, respectively, using tissue-weighting factors from ICRP-89. The toxicity study detected no changes in the organ or whole-body weight, food consumption, haematologic or clinical chemistry parameters. Moreover, lesions or abnormalities were not found during the histopathological examination. Conclusion: The toxicological evaluation of SRF101 verified the biosafety of the radiotracer for human administration. The dosimetry calculations revealed that the radiation-associated risk of [18F]SRF101 would be of the same order as other 18F radiopharmaceuticals used in clinical applications. These study findings confirm that the novel radiotracer would be safe for use in human PET imaging.

Background: 1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole ([18F]FAZA) is manufactured by nucleophilic radiofluorination of 1-α-D-(2’,3’-di-O-acetyl-5’-O-toluenesulfonylarabinofuranosyl)- 2-nitroimidazole (DiAcTosAZA) and alkaline deprotection to afford [18F]FAZA. High yields (>60%) under optimized conditions frequently revert to low yields (<20%) in large scale, automated syntheses. Competing side reactions and concomitant complex reaction mixtures contribute to substantial loss of product during HPLC clean-up. Objective: To develop alternative precursors for facile routine clinical manufacture of [18F]FAZA that are compatible with current equipment and automated procedures. Methods: Two new precursors, 1-α-D-(2’,3’-di-O-acetyl-5’-O-(4-nitrobenzene)sulfonyl-arabinofuranosyl)-2- nitroimidazole (DiAcNosAZA) and 1-α-D-(2’,3’-di-O-acetyl-5’-iodo-arabinofuranosyl)-2-nitroimidazole (DiAcIAZA), were synthesized from commercially-available 1-α-D-arabinofuranosyl-2-nitroimidazole (AZA). A commercial automated synthesis unit (ASU) was used to condition F-18 for anhydrous radiofluorination, and to radiofluorinate DiAcNosAZA and DiAcIAZA using the local standardized protocol to manufacture [18F]FAZA from AcTosAZA. Results: DiAcNosAZA was synthesized via two pathways, in recovered yields of 29% and 40%, respectively. The nosylation of 1-α-D-(2’,3’-di-O-acetyl-arabinofuranosyl)-2-nitroimidazole (DiAcAZA) featured a strong competing reaction that afforded 1-α-D-(2’,3’-di-O-acetyl-5’-chloro-arabinofuranosyl)-2- nitroimidazole (DiAcClAZA) in 55% yield. Radiofluorination yields were better from DiAcNosAZA and DiAcIAZA than from DiAcTosAZA, and the presence of fewer side products afforded higher purity [18F]FAZA preparations. Several radioactive and non-radioactive by products of radiofluorination were assigned tentative chemical structures based on co-chromatography with authentic reference compounds. Conclusion: DiAcClAZA, a major side-product in the preparation of DiAcNosAZA, and its deprotected analogue (ClAZA), are unproven hypoxic tissue radiosensitizers. DiAcNosAZA and DiAcIAZA provided good radiofluorination yields in comparison to AcTosAZA and could become preferred [18F]FAZA precursors if the cleaner reactions can be exploited to bypass HPLC purification.

Background: Alzheimer’s disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice. Methods: Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aplaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice. Results: The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aβ-peptide, mainly through π-π interactions. According to a dynamic simulation study the ligand-Aβ peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aβ plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model. Conclusion: The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aβ senile plaques.

Background: Radiotherapy is one of the treatment methods for cancers using ionizing radiations. About 70% of cancer patients undergo radiotherapy. Radiation effect on the skin is one of the main complications of radiotherapy and dose limiting factor. To ameliorate this complication, we used melatonin as a radioprotective agent due to its antioxidant and anti-inflammatory effects, free radical scavenging, improving overall survival after irradiation as well as minimizing the degree of DNA damage and frequency of chromosomal abrasions. Methods: Sixty male Wistar rats were randomly assigned to 4 groups: control (C), melatonin (M), radiation (R) and melatonin + radiation (MR). A single dose of 30 Gy gamma radiation was exposed to the right hind legs of the rats while 40 mg/ml of melatonin was administered 30 minutes before irradiation and 2 mg/ml once daily in the afternoon for one month till the date of rat’s sacrifice. Five rats from each group were sacrificed 4, 12 and 20 weeks after irradiation. Afterwards, their exposed skin tissues were examined histologically and biochemically. Results: In biochemical analysis, we found that malondialdehyde (MDA) levels significantly increased in R group and decreased significantly in M and MR groups after 4, 12, and 20 weeks, whereas catalase (CAT) and superoxide dismutase (SOD) activities decreased in the R group and increased in M and MR groups during the same time periods compared with the C group (p<0.05). Histopathological examination found there were statistically significant differences between R group compared with the C and M groups for the three different time periods (p<0.005, p<0.004 and p<0.004) respectively, while R group differed significantly with MR group (p<0.013). No significant differences were observed between C and M compared with MR group (p>0.05) at 4 and 20 weeks except for inflammation and hair follicle atrophy, while there were significant effects at 12 weeks (p<0.05). Conclusion: Melatonin can be successfully used for the prevention and treatment of radiation-induced skin injury. We recommend the use of melatonin in optimal and safe doses. These doses should be administered over a long period of time for effective radioprotection and amelioration of skin damages as well as improving the therapeutic ratio of radiotherapy.

Objective: Stable and non-radioactive isotope labeled compounds gained significance in recent drug discovery and other various applications such as bio-analytical studies. The modern bioanalytical techniques can study the adverse therapeutic effects of drugs by comparing isotopically labeled internal standards. A well-designed labeled compound can provide high-quality information about the identity and quantification of drug-related compounds in biological samples. This information can be very useful at key decision points in drug development. In this study, we tried to synthesize Nilutamide- d6 which can be useful to study the adverse effects of Nilutamide, and based on these can modify or widen the new drug derivatives. Nilutamide is a nonsteroidal antiandrogen which is used in the treatment of prostate cancer. The aim of this study was to develop a synthetic approach to prepare deuterium labeled [2H6]-5, 5-dimethylimidazolidine-2, 4-dione and [2H6]-nilutamide. Methods: Since nilutamide is a derivative of hydantoin, it involves the synthesis of Dimethylhydantoin via Bucherer-Bergs hydantoin synthesis, followed by oxidative N-arylation with 4-iodo-1-nitro-2- (trifluoromethyl) benzene. Conclusion: We successfully synthesized [2H6]-nilutamide and [2H6]-dimethylhydantoin with good isotopic purity, measured to be of adequate quality for use as internal standards in bio-analytical studies. A brief mechanistic study of Bucherer-Bergs hydantoin reaction was carried and the reason for possible H/D exchange was explained.

Objective: Glioblastoma multiforme (GBM) represents the most common and malignant glioma, accounting for 45%-50% of all gliomas. The median survival time for patients with glioblastoma is only 12-15 months after surgical, chemioterapic and radiotherapic treatment; a correct diagnosis is naturally fundamental to establish a rapid and correct therapy. Non-invasive imaging plays a pivotal role in each phase of the diagnostic workup of patients with suspected for diagnosis. The aim of this case report was to describe the potential clinical impact of 18F-fluorocholine (FCH) PET/CT in the assessment of a cystic GBM mimicking a spontaneous hemorrhage. Methods: a 57 years-old male with intraparenchymal hemorrhage at CT imaging initially in reduction ad serial imaging and suspected right fronto-temporo-parietal lesion at MRI underwent dynamic and static (60' after tracer injection) FCH PET/CT of the brain. Results: FCH PET/CT showed rapid tracer uptake after few second from injection at dynamic acquisition and consequent incremental mild uptake at static imaging after 60 minutes at the level of oval formation in the right cerebral hemisphere characterized by annular and peripheral high metabolic activity. The central region of the lesion was characterized by the absence 18F-FCH uptake most likely due to blood component. The patient underwent surgery for tumor removal; the histopathological examination confirmed the suspect of GBM. Chemo-radiotherapic adjuvant protocol according to Stupp protocol was therefore administrated; to date the patient is alive without any progression disease at 5 months from treatment. Conclusion: In this case report FCH PET/CT represented the final diagnostic technique to confirm the suspicious of a cystic GBM. Our case demonstrated the potential role of 18F-FCH PET/CT for discrimination of higher proliferation area over intraparenchymal hemorrhage, supporting the potential use of this imaging biomarker in surgical or radiosurgical approach. Obviously, further prospective studies are needed to confirm this role and to exactly define possible routinely applications.