Current Radiopharmaceuticals - Volume 14, Issue 2, 2021

Thyroid carcinoma represents a complex pathology that can still be considered a medical challenge, despite having a better prognosis and life expectancy than most other neoplasms; also the scenario of multiple malignancies involving thyroid cancer is nowadays a common reality. Materials and methods: We reviewed the literature regarding the aggressive presentation of synchronous thyroid and breast cancer. In the current paper, we report the case of a 59 years-old woman, diagnosed with invasive ductal breast carcinoma and papillary thyroid carcinoma, presenting a natural history of both aggressive synchronous tumors. At the moment of hospitalization, the diagnosis was breast carcinoma with multiple secondary lesions, suggestive of lung and bone metastases, and nodular goiter. Results: Searching the literature in PUBMED with the terms “thyroid carcinoma and synchronous breast carcinoma, we found 86 studies; introducing the term “aggressive,” the result included 4 studies, among which, none showed to be relevant to the terms aggressive and synchronous. A similar search was done in SCOPUS finding 92 documents and after introducing the term aggressive, the number of papers was 8, none including the literature on synchronous aggressive metastatic thyroid and breast carcinoma. A majority of imaging diagnostic tools were used in this particular medical case in order to ensure the best potential outcome. The final diagnosis was papillary thyroid carcinoma with lung and unusual multiple bone metastases and synchronous invasive ductal breast carcinoma with subcutaneous metastases. Conclusion: The case illustrates the challenges in the correct assessment of oncologic patients, despite the advances in medical imaging and technologies and underlines the essential role of nuclear medicine procedures in the diagnostic and therapy protocols.

The development of new radiolabeled Positron emission tomography tracers has been extensively utilized to access the increasing diversity in the research process and to facilitate the development in research methodology, clinical usage of drug discovery and patient care. Recent advances in radiochemistry, as well as the latest techniques in automated radio-synthesizer, have encouraged and challenged the radiochemists to produce the routinely developed radiotracers. Various radionuclides like 18F, 11C, 15O, 13N 99mTc, 131I, 124I and 64Cu are used for incorporating into different chemical scaffolds; among them, 18F and 11C tagged radiotracers are mostly explored such as 11C-Methionine, 11C-Choline, 18F-FDG, 18F-FLT, and 18F-FES. This review is focused on the development of radiochemistry routes to synthesize different radiotracers of 11C and 18F for clinical studies.

Background: One of the challenges in positron emission tomography (PET) is labelling complex aliphatic molecules. Objective: This study aimed to develop a method of metal-catalysed radiofluorination that is site-selective and works in moderate to good yields under facile conditions. Methods: Herein, we report on the optimisation of an aliphatic C-H to C-¹⁸F bond transformation catalysed by a Mn(porphyrin) complex. Results: The successful oxidation of 11 aliphatic molecules, including progesterone, is reported. Radiochemical Incorporations (RCIs) up to 69% were achieved within 60 min without the need for pre-activation or special equipment. Conclusion: The method features mild conditions (60 °C) and promises to constitute a valuable approach to labelling of biomolecules and drug substances.

Background: Diagnostic nuclear medicine reveals physiological processes in vivo, facilitating early detection of disease prior to anatomical changes. However, in pediatric studies, the selection of appropriate dosing guidelines is challenging. Administration of Radioactive Substances Advisory Committee (ARSAC) and North American Consensus (NAC) guidelines are extensively used. Objective: To determine appropriate pediatric dosing guideline for a South African Tertiary Hospital (SATH). Methods: A combination of retrospective and empirical studies was conducted. Age, weight, name of the nuclear medicine study and administered activities were extracted from archived pediatric patients’ files in a SATH who were attended from 2012-2015. To increase the sample size when calculating would be administered activities based on ARSAC and NAC guidelines, weights for sixty pediatric patients (empirical data) from the commonly conducted nuclear medicine studies were used. Results: The most commonly performed nuclear medicine studies at a SATH were bone scans, ^99mTc-HIDA scans, renal scans, thyroid scans, MIBG scans and gastroesophageal reflux scans. The mean pediatric administered radiopharmaceutical activities based on SATH, ARSAC and NAC guidelines were; bone scans (57.7, 15.2 and 10.0 MBq/kg), ^99mTc-HIDA scans (13.7, 5.0 and 3.6 MBq/kg), renal scans (13.9, 3.4 and 7.8 MBq/kg), thyroid scans (7.0, 2.6 and 1.5 MBq/kg), MIBG scans (15.5, 15.1 and 7.7 MBq/kg) and gastroesophageal reflux scans (2.1, 1.9 and 1.7 MBq/kg). High variability of Administered Radiopharmaceutical Activities (ARAs) was observed for SATH guidelines compared to ARSAC and NAC guidelines. Conclusion: NAC guidelines are recommended for dosing pediatric patients at SATH. These guidelines will certainly reduce pediatric doses, which are currently high.

Background : The development of resolution recovery (RR) algorithms has made it possible to preserve the good quality of cardiac images despite a reduced number of counts during study acquisition. Objective: Our purpose was to evaluate the performance of three different software packages in the quantification of left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) from gated perfusion SPECT, applying a resolution recovery (RR) algorithm (GE Myovation Evolution), with respect to cardiac MRI (cMRI) as a gold standard. Methods: We retrospectively enrolled 21 patients, with suspected or known coronary heart disease. Images at rest were reconstructed by filtered back projection (FBP) and by an iterative protocol with the RR algorithm. EDV, ESV, and LVEF were automatically computed employing Quantitative Gated SPECT (QGS), Myometrix (MX), and Corridor 4DM (4DM). Any difference in EDV, ESV, and LVEF calculation between cMRI and the three packages (with FBP and iterative reconstruction with RR) was tested using Wilcoxon or paired t-test, with the assumption of normality assessed using the Shapiro-Wilk test. Agreement between imaging reconstruction algorithms and between gated-SPECT software packages and cMRI was studied with Pearson’s (r) or Spearman’s (R) correlation coefficients and Lin’s concordance correlation coefficient (LCC). Results: Intra-software evaluation always revealed very strong correlation coefficients (R, r ≥ 0.8) and excellent LCC coefficients (LCC > 0.95), except for the LCC coefficient between MX-FBP and MX-RR in EDV evaluation, nevertheless considered very good (LCC = 0.94). EDV and ESV had significantly lower value when calculated with the RR algorithm with respect to FBP reconstruction in QGS and MX. LVEF estimation did not show significant differences for QGS-FBP, QGS-RR, MX, and 4DM-RR with respect to cMRI. Conclusion: All reconstruction methods systematically underestimate EDV and ESV, with higher underestimation applying only the RR. No significant differences were observed between 4DM - RR and 4DM-FBP, for each parameter, when the 4DM package was used.

Background: Due to its overexpression in a variety of tumor types, the chemokine receptor 4 (CXCR4) represents a highly relevant diagnostic and therapeutic target in nuclear oncology. Recently, [⁶⁸Ga]Ga-DOTA-Pentixafor has emerged as an excellent imaging agent for positron emission tomography (PET) of CXCR4 expression in vivo. Preparation conditions may influence the quality and in vivo behaviour of this tracer and no standard procedure for the quality controls (QCs) is available. Objective: The developed analytical test method was validated because a specific monograph in the Pharmacopoeia is not available for [68Ga]Ga-DOTA-Pentixafor. Method: A stepwise approach was used based on the quality by design (QbD) concept of the ICH Q2 (R1) and Q8 (Pharmaceutical Development) guidelines in accordance with the regulations and requirements of EANM, SNM, IAEA and WHO. Results: The purity and quality of the radiopharmaceutical obtained according to the proposed method were found to be high enough to safely administrate it to patients. Excellent linearity was found between 0.5 and 4 μg/mL, with a correlation coefficient (r²) for calibration curves being equal to 0.999, the average coefficient of variation (CV%) < 2% and average bias% that did not deviate more than 5% for all concentrations. Conclusion: This study developed a new rapid and simple HPLC method of analysis for the routine QCs of [⁶⁸Ga]Ga-DOTA-Pentixafor to guarantee the high quality of the finished product before release.

Background: Organic solvents play an indispensable role in most of the radiopharmaceutical production stages. It is almost impossible to remove them entirely in the final formulation of the product. Objective: In this presented work, an analytical method by gas chromatography coupled with flame ionization detection (GC-FID) has been developed to determine organic solvents in radiopharmaceutical samples. The effect of injection holding time, temperature variation in the injection port, and the column temperature on the analysis time and resolution (R ≥ 1.5) of ethanol and acetonitrile was studied extensively. Methods: The experimental conditions were optimized with the aid of further statistical analysis; thence, the proposed method was validated following the International Council for Harmonisation (ICH) Q2 (R1) guideline. Results: The proposed analytical method surpassed the acceptance criteria including the linearity > 0.990 (correlation coefficient of R²), precision < 2%, LOD, and LOQ, accuracy > 90% for all solvents. The separation between ethanol and acetonitrile was acceptable with a resolution R > 1.5. Further statistical analysis of Oneway ANOVA revealed that the increment in injection holding time and variation of temperature at the injection port did not significantly affect the analysis time. Nevertheless, the variation in injection port temperature substantially influenced the resolution of ethanol and acetonitrile peaks (p < 0.05). Conclusion: The proposed analytical method has been successfully implemented to determine the organic solvent in the [¹⁸F]fluoro-ethyl-tyrosine ([¹⁸F]FET), [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO), and [¹⁸F]fluorothymidine ([¹⁸F]FLT).

Background: Patients with advanced-stage ovarian cancer face a poor prognosis because of recurrent peritoneal cavity metastases following surgery and chemotherapy. Alpha-emitters may enable the efficient treatment of such disseminated diseases because of their short range and highly energetic radiation. Radium-224 is a candidate α-emitter due to its convenient 3.6-day half-life, with more than 90% of the decay energy originating from α-particles. However, its inherent skeletal accumulation must be overcome to facilitate intraperitoneal delivery of the radiation dose. Therefore, ²²⁴Ra-labeled CaCO3 microparticles have been developed. Objective: The antitumor effect of CaCO3 microparticles as a carrier for ²²⁴Ra was investigated, with an emphasis on the ratio of activity to mass dose of CaCO3, that is, specific activity. Methods: Nude athymic mice were inoculated intraperitoneally with human ovarian cancer cells (ES-2) and treated with a single intraperitoneal injection of ²²⁴Ra-labeled CaCO3 microparticles with varying combinations of mass and activity dose, or cationic ²²⁴Ra in solution. Survival and ascites volume at sacrifice were evaluated. Results: Significant therapeutic effect was achieved for all tested specific activities ranging from 0.4 to 4.6 kBq/mg. Although treatment with a mean activity dose of 1305 kBq/kg of cationic ²²⁴Ra prolonged the survival compared with the control, equivalent median survival could be achieved with ²²⁴Ra-labeled microparticles with a mean dose of only 420 kBq/kg. The best outcome was achieved with the highest specific activities (2.6 and 4.6 kBq/mg). Conclusion: Radium-224-labeled CaCO3 microparticles present a promising therapy against cancer dissemination in body cavities.

Background: Rheumatoid arthritis (RA) is an inflammatory chronic disease characterized by inflammation, pain, swelling and disability, and radiosynovectomy is one of the disease treatment lines. In this study, the possibility of providing rhenium-186/rhenium-188 chitosan radiopharmaceuticals, optimization of conditions for their production and bio-distribution are reported. Objective: In order to build perrhenic acid for labeling, natural rhenium was exposed to radiation. Radionuclidic and radiochemical purities of (186/188Re)-NaReO4 were examined by gamma spectroscopy and paper chromatography methods, respectively. Methods: Labeling of chitosan with rhenium was done in different acidic situations. The radiochemical purity 186/188Re-chitosan was applied by radio thin layer chromatography (RTLC). Lastly, the bio-distribution of the radiolabeled chitosan was studied in various organs after intra articular injection of the complex to lab rats. Gamma spectrometry confirmed the high rhenium radionuclidic purity. Chromatography results showed that perrhenic acid was produced with purity greater than 97% and rhenium chitosan labeling was done over 98% in pH = 3. Dissection results showed a high bio-distribution of 186/188Re-chitosan after injection into the joint with no leakage to surrounding organs. Conclusion: According to the results, there is a possibility of labeling rhenium with chitosan in very high radiochemical purity. Regarding the high retention of these radiopharmaceuticals in joints with no leakage to surrounding organs, 186/188Re-chitosan can be applied as new radiosynovectomy drugs for rheumatoid arthritis treatment.

Background: Radioguided surgery represents a validated technique for the detection and the excision of abnormal parathyroid glands responsible for primary hyperparathyroidism (PHPT). To date little attention has been paid as to how the characteristics of gamma-probes can influence surgical procedure and time, thus having an impact on postoperative morbidity, hospitalization and costs. Methods: We designed a new prototype of gamma-probe, the Gonioprobe, and tested its clinical utility in the operating room. Gonioprobe, thanks to its 5 scintillating independent crystals, performs the dual function of Navigator and Lock-on-target. These characteristics allow the immediate guidance of the surgeon’s hand towards the source with very high precision, and with a much higher spatial resolution than commercial probes. Gonioprobe was used during intervention to detect abnormal parathyroid tissue, and to ensure no radioactivity in surgery bed after adenoma removal. Results: We tested our gamma-probe on parathyroid adenomas particularly difficult to identify at a visual inspection due to anatomy modifications from previous neck surgery and/or characterized by uncommon localization. Moreover, parathyroid adenomas were hardly removable due to the proximity to the esophagus, neck vessels and/or recurrent laryngeal nerve (RLN). An intraoperative nerve monitoring system was used to protect the recurrent laryngeal nerve from injuries. Parathyroid hormone (PTH) assay and frozen biopsy confirmed the successful excision of the adenomas. Conclusion: The intraoperative use of the innovative Gonioprobe along with the nerve monitoring system allowed an accurate and safe removal of parathyroid adenomas and offered a significant advantage by reducing surgical time and postoperative complications, as well as hospitalization and costs.