Current Radiopharmaceuticals - Volume 9, Issue 3, 2016

There are new efforts to develop “sugar” probes for molecular imaging focusing on human clinical studies. Radiolabeled carbohydrates are used as substrate probes for studying specific processes in tissues and organisms. The best application case is 2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG), which is incorporated by cancer cells. The introduction of 18F-FDG has advanced enormously human Positron Emission Tomography (PET). This review focuses on the importance of 18FFDG and other sugars as imaging probes in PET and Single Photon Emission Computed Tomography (SPECT) imaging. In conclusion, new radiolabeled molecules that can be used as radiopharmaceuticals also would possibly help in the treatment of cancer cells in human patients.

Over the past several years, Positron Emission Tomography (PET) imaging agents labeled with 68Gallium (68Ga) have undergone a significant increase in clinical utilization. 68Ga is conveniently produced from a germanium-68/gallium-68 (68Ge/68Ga) generator. Because of the compact size and ease of use of the generator, 68Ga labeled compounds may be more cost-effective than PET radioisotopes that are cyclotron-produced. The convenient half-life of 68Ga (T1/2=68 min) provides sufficient radioactivity for various PET imaging applications, while delivering acceptable radiation doses to patients. This chapter summarizes the emerging clinical utilization of 68Ga-based radiotracers in medical imaging.

Introduction: Gallium-68 citrate has been successfully applied in the PET imaging of infections and inflammation in some centers; however further evaluation of the tracer in inflammation models is of great importance. Methods: 68Ga-citrate prepared from [68Ga]GaCl3 (eluted form an SnO2 based 68Ge/68Ga generator) and sodium citrate at optimized conditions followed by quality control tests was injected to normal and turpentine-oil induced rats PET/CT imaging studies up to 290 min. Results: 68Ga-citrate was prepared with acceptable radiochemical purity (>99 ITLC, >99% HPLC), specific activity (28-30 GBq/mM), chemical purity (Sn, Fe <0.3 ppm; Zn<0.2 ppm) in 15 min at 50°C. PET/CT imaging of the tracer demonstrated early detection of inflamed site in animal models in 60-80 min. Conclusion: This study demonstrated possible early detection of inflammation foci in vivo using 68Ga-citrate prepared using commercially available 68Ge/68Ga generators for PET imaging.

Background: Previously, we have labeled doxorubicin with [99mTc] and evaluated its potential as a SPECT agent to detect cancer in tumor bearing mice. In this study, we sought to radiolabel doxorubicin with [18F] using acylation method. Methods: A quaternary salt of the precursor pentamethylbenzyl-4-(trimethylammonium trifluoromethanesulfonate) benzoate was synthesized and characterized by 1H-NMR. As a first step, 4-[18F]- fluorobenzoic acid (FBA) was synthesized from precursor. In second step, [18F]-FBA was further converted to its corresponding acyl form to radiolabel doxorubicin via acylation reaction. Results: The total reaction time for the synthesis of [18F]-fluorobenzoate-doxorubicin was about 60 minutes. The radiolabeling efficiency of the final product was estimated to be about 59.0% The radiochemical yield for the synthesis of [18F]-FBA and [18F]-fluorobenzoate-doxorubicin were 19.0- 29.0% and 12.0-14.0% respectively. Conclusion: Radio synthesis of [18F]-fluorobenzoate-doxorubicin by acylation is a convenient method. However, further improvement in the labeling strategy is required to increase the radiolabeling efficiency and radio synthesis yield. Also, the radiolabeled product needs a detailed pre-clinical evaluation.

Background and Objective: Pancreatic cancer is very common and difficult to diagnose in early stage. Imaging systems for diagnosing cancer have many disadvantages. However, combining different imaging modalities offers synergistic advantages. Optical imaging is the most multidirectional and widely used imaging modality in both clinical practice and research. Methods: In present study, Zinc(II) phthalocyanine [Zn(II)Pc] was synthesized, labeled with iodine- 131 and in vitro study was carried out. The intracellular uptake studies of radiolabeled Zn(II)Pc were performed in WI-38 [ATCC CCL-75™, tissue: human fibroblast lung] and MIA PaCa-2 [ATCC CRL-1420™, tissue: human epithelial pancreas carcinoma] cell lines. Results: The intracellular uptake efficiency of radiolabeled Zn(II)Pc in MIA PaCa-2 cells was determined two times higher than WI-38 cells. Also, fluorescence imaging (FI) efficiency of synthesized Zn(II)Pc was investigated in MIA PaCa-2 cells and significant uptake was observed. Conclusion: Zn(II)Pc might be used as a new agent for dual fluorescence/nuclear imaging for pancreatic cancer.

Background: 18F-FDG-PET/CT applications in the field of differentiated thyroid cancer (DTC) are continuously growing. Objective: To retrospectively analyze in a wide population enrolled in two nuclear medicine centers the diagnostic value of 18F-FDG-PET/CT in patients treated with 131I and negative 131I-WBS but in presence of Tg levels higher than 1ng/ml after TSH stimulation. Method: From September 2005 to December 2014, 154 patients affected by DTC, treated with 131I with negative 131I-WBS and Tg≥1ng/ml underwent 18F-FDG-PET/CT. Results: 66 patients (43%) had a negative 18F-FDG-PET/CT (mean Tg=7.7ng/ml; SD=9.6) and 88 (57%) a positive scan (mean Tg=169.4; SD=294.6) documenting bone, pulmonary, lymph-node metastases and local recurrences. There was no statistically significant correlation between 18F-FDGPET/ CT results and sex, previous lymphadenectomy, the “on-” or “off-therapy” state; on the contrary, there was a statistically significant correlation between PET results and primary tumor size (T1–T2 vs. T3–T4). ROC analysis showed that the highest accuracy in terms of best compromise between sensitivity and specificity (sensitivity= 71,6%; specificity=92,4%; AUC area under the curve= 0.807) is achieved when the 12ng/mL is considered the Tg cut-off value to interpret the results. Conclusion: Our study confirm in a wide population that 18F-FDG-PET/CT is useful in evaluating patients affected by DTC, negative 131I-WBS and Tg>1ng/ml, identifying 12ng/ml as the Tg level cut-off over which is better to perform the study.

Background and Objective: The hypoxia PET tracer, 1-[18F]fluoro-3-(2-nitro-1Himidazol- 1-yl)-propan-2-ol ([18F]FMISO) is the first radiotracer developed for hypoxia PET imaging and has shown promising for cancer diagnosis and prognosis. However, access to [18F]FMISO radiotracer is limited due to the needed cyclotron and radiochemistry expertise. The study aimed to develop the automated production method on the [18F]FMISO radiotracer with the novel fully automated platform of the BG75 system and validate its usage on animal tumor models. Method: [18F]FMISO was produced with the dose synthesis cartridge automatically on the BG75 system. Validation of [18F]FMISO hypoxia imaging functionality was conducted on two tumor mouse models (FaDu/U87 tumor). The distribution of [18F]FMISO within tumor was further validated by the standard hypoxia marker EF5. Results: The average radiochemical purity was (99±1) % and the average pH was 5.5±0.2 with other quality attributes passing standard criteria (n=12). Overall biodistribution for [18F]FMISO in both tumor models was consistent with reported studies where bladder and large intestines presented highest activity at 90 min post injection. High spatial correlation was found between [18F]FMISO autoradiography and EF5 hypoxia staining, indicating high hypoxia specificity of [18MF]FMISO. Conclusion: This study shows that qualified [18F]FMISO can be efficiently produced on the BG75 system in an automated “dose-on-demand” mode using single dose disposable cards. The possibilities of having a low-cost, automated system manufacturing ([18F]Fluoride production + synthesis + QC) different radiotracers will greatly enhance the potential for PET technology to reach new geographical areas and underserved patient populations.

Purpose: The aim of the study was to determine the correlation between 16α-18F-fluoro- 17β-estradiol (18F-FES) uptake and the expression and functionality of estrogen receptors (ERs), as well as to evaluate the ability of 18F-FES PET to predict the response to hormonal therapy (HT) in patients with locally advanced or metastatic breast cancer (BC). Methods: Literature searches in the major literature databases were carried out in order to select English-language articles dealing with 18F-FES PET and BC. Studies that included patients with BC undergoing 18F-FES PET alone or in combination with other imaging modalities and included the absolute numbers of true-positive, true-negative, false-positive and false-negative test results were selected. Results: We found 23 journal articles, published between 1988 and December 2014, that critically evaluated the role of 18F-FES PET in BC patients. Two separate meta-analyses were carried out: 1- to assess the correlation between 18F-FES uptake and ER expression and 2- to determine the predictive value of 18F-FES in response to HT. For the first, we considered nine selected studies with a total of 238 patients. A pooled sensitivity of 82% (95% CI: 74-88%) and a pooled specificity of 95% (95% CI: 86-99%) for the evaluation of ER functional status by 18F-FES PET were found. Seven studies, with a total of 226 patients, were considered eligible for the analysis of prediction for response. The pooled sensitivities and specificities were 63.9% (95% CI: 46.2-79.2%) vs. 66.7% (95% CI: 52.1-79.2%), and 28.6% (95% CI: 17.3-42.2%) vs. 62.1% (95% CI: 48.4-74.5%), for a SUV cutoff of 1.5 and 2.0, respectively. Conclusion: A good correlation between 18F-FES uptake and ER expression by immunohistochemistry emerges, while the role of 18F-FES in predicting the response to endocrine therapy in advanced BC remains undetermined.

Purpose: Gioblastoma multiforme as a chemoresistant and radioresistant malignant cell line needs to novel strategies to treatment. Low-dose hyper-radiosensitivity (LDHRS) seems to be an effective phenomenon to irradiation that can save normal brain fibroblasts. Genistein which is a soy isoflavone can be cytotoxic in some tumor cell lines. So we determined to study the effect of combining these two treatment modalities. Materials and Methods: After 30 hours incubation with Genistein in different concentrations on U87MG cell line, proliferation and clonogenicity were conducted by both clonogenic and MTT assays. A conventional 2Gy radiation dose was compared with 10 doses of 0.2Gy gamma irradiation with 3 minutes and 1 hour intervals. Finally, concurrent effect of these modalities was assessed. Results: Based on acquired cell doubling time (30 hours), one doubling time treatment by Genistein could decrease clonogenicity. U87MG cell line exhibited HRS at low dose irradiations. 2Gy irradiation was more effective than ultra-fractionation methods in comparison with control group. All groups with 50uM concentration of Genistein showed decrease in the survival. This decrease compared with control group, in 10x0.2Gy with 3 minutes intervals plus 50uM Genistein was significant and for groups with the same dose of Genistein but along with continuous 2Gy was more significant. Conclusion: In one day treatment regimen, 10x0.2Gy ultra-fractionation with 3 minutes and 1 hour intervals seems to be less effective than conventional 2Gy irradiation, however adding 50uM Genistein can decrease survival more. Although 2Gy conventional dose plus 50uM Genistein was the most effective regimen.