Current Radiopharmaceuticals - Volume 13, Issue 2, 2020

Background: To date, several meta-analyses and systematic reviews have reported data about the prevalence and risk of malignancy of thyroid incidentalomas detected by different PET radiopharmaceuticals. Objective: This article aims to summarize the published evidence-based data about the prevalence and risk of malignancy of thyroid incidentalomas detected by different PET radiopharmaceuticals. Methods: A comprehensive computer literature search of systematic reviews and meta-analyses published up to July 2019 in PubMed/MEDLINE and Cochrane library databases regarding the prevalence and risk of malignancy of thyroid incidentalomas detected by different PET radiopharmaceuticals was carried out. Results: We have summarized the data about prevalence and risk of malignancy of thyroid incidentalomas detected by different PET radiopharmaceuticals (fluorine-18 fluorodeoxyglucose, radiolabelled choline and prostate-specific membrane antigen) taking into account 8 evidence-based articles. Conclusion: Evidence-based data demonstrated that thyroid incidentalomas detected by different PET radiopharmaceuticals are not infrequent and their risk of malignancy is not negligible, in particular if focal pattern is evident at PET, thus requiring further clinical and instrumental evaluation.

Background: Radiolabeled prostate-specific membrane antigen PSMA-based PET/CT or PET/MRI is a whole-body imaging technique currently performed for the detection of prostate cancer lesions. PSMA has been also demonstrated to be expressed by the neovasculature of many other solid tumors. Objective: The aim of this review is to evaluate the possible diagnostic role of radiolabeled PSMA PET/CT or PET/MRI in patients with gliomas and glioblastomas, by summarizing the available literature data. Methods: A comprehensive literature search of the PubMed/MEDLINE, Scopus, Embase and Cochrane library databases was conducted to find relevant published articles about the diagnostic performance of radiolabeled PSMA binding agents in PET/CT or PET/MRI imaging of patients with suspected gliomas or glioblastomas. Results: Seven case reports or case series and 3 studies enrolling more than 10 patients showed that gliomas and glioblastoma are PSMA-avid tumors. Conclusion: Radiolabeled PSMA imaging seems to be useful in analyzing glioma/glioblastoma. Further studies enrolling a wider population are needed to clarify the real clinical and diagnostic role of radiolabeled PSMA in this setting and its possible position in the diagnostic flow-chart.

Background: The Hemiscorpius lepturus (H. lepturus) is a deadly scorpion species living in the southern Iran. Objective: H. lepturus induces delayed toxicity symptoms and understanding the long term biodistribution/ biokinetic of the venom is of great interest in toxicology. Methods: A Ga-67 labeled venom was prepared using a DOTA -conjugated venom followed by radiolabeling using 67GaCl3 at 40°C for 90 min. The purification of the radiolabeled venom was performed using size exclusion-chromatography (radiochemical purity 71%). The radiolabeled venom was stable in the final solution in the presence of human serum at 37°C for 72 hours. The tissue distribution was studied in blood, heart, liver, spleen, muscle, brain, kidney, intestine and skin tissues at the intervals of 1, 4, 24, 48 and 72 hours using tissue counting and SPECT imaging. Results: The radiolabeled venom mixture obtained with an estimated molar activity of 0.52 MBq/μg. The main accumulation tissues during the first 72 hours were kidneys, blood, liver, intestines, stomach and skin, respectively. Therefore, it is likely that H. lepturus’ clinical effects and renal toxicity are primary and caused by direct effects of the H. lepturus venom. Conclusion: The results have largely shown the direct clinical effects on the studied tissues during the 72-hour period and antivenom administration can strongly alleviate the toxicity effects as early as 72 hours in the management of the patients.

Background: The radiolabelling of receptor-binding peptides for therapy is a challenge since the peptide itself is exposed (during labelling, storage and transport) to radiation-induced damage, directly or indirectly, in aqueous solution. Hence, the use of radiostabilizers seems to be mandatory, especially in peptide molecules that contain radiation-sensitive amino acids. Objective: The aim of this study was to investigate the effect of two stabilizers, gentisic acid and methionine, to delve into how each of them affects the radiolabelling and stability of the minigastrin analogue [177Lu]Lu-DOTA-His-His-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 through the analysis of the 22 species distinguished over time by an optimized HPLC system. Methods: The stabilizers, in different combinations, were present from the beginning of the labelling process carried out at 96 °C for 15 min. The stability was studied for up to 7 days. Results: The unexpected selective oxidation of the methionine residue of the radiolabelled peptide, promoted by gentisic acid, led to studying the effect of pH, from 3.5 to 6.0, in the presence of only this stabilizer. A pH-dependent antioxidant behaviour was revealed, showing a decrease in peptide impurities but an increase in the selective oxidation as the pH was increased. Conclusion: The selective oxidation of the methionine residue could be induced by oxidizing species probably produced in the reaction between gentisic acid and free radicals of water, during the protection of the radiolabelled peptide from the attack of these harmful species. Therefore, the addition of methionine becomes necessary to effectively decrease this selective oxidation in the methioninecontaining peptide.

Background: The use of 123I-mIBG has been approved for decades for Parkinson’s disease (PD) diagnosis and as a predictor of mortality and potentially fatal events in patients with Heart Failure (HF). The standardized technique includes an early acquisition (15 minutes from injection), and a late acquisition (240 minutes). Early images mainly represent interstitial uptake, whereas delayed images represent actual neuronal uptake, however, it is reasonable to affirm that different pathological situations, such as PD and HF, imply a different meaning for early and late imaging. Objective: This prospective study aims to investigate the clinical usefulness of an immediate planar 123I-mIBG image acquisition (5 minutes) both in patients with PD and in patients with HF. Methods: 115 patients referred to 123I-mIBG cardiac imaging in Nuclear Medicine Center have been enrolled (60 patients with PD, absence of diabetes and/or cardiologic pathology, Hoehn e Yahr classification ≤ 1.5; 55 patients with cardiomyopathy, diagnosis of HF, NYHA class I–III). 123I-mIBG planar anterior thoracic acquisitions were performed after 5 (immediate), 15 (early) and 240 (late) minutes from injection and H/M ratios were calculated. Results: In PD group H/M mean values resulted in 1.58±0.22 for immediate (5 min), 1.61±0.26 for early (15 min) and 1.59±0.37 for late (240 min) acquisitions. In the HF group, H/M mean values resulted in 1.63±0.24 for immediate (5 min), 1.65±0.22 for early (15 min) and 1.57±0.17 for late (240 min) acquisitions, respectively. H/M values obtained at 5 min and 15 min are provided similar results, with no statistical difference (p = ns) regardless of the pathology examined (PD or HF groups). The statistical analyses validated the diagnostic role of immediate acquisition (5 min) and early acquisition (15 min) in PD group as compared to the standardized late acquisition (240 min). On the contrary, in HF group, immediate and early acquisition, as compared to late acquisition (240 min), is not validated as a major cardiac events predictor. Conclusion: Our results indicate the potential role of immediate (5 min) or early (15 min) acquisition in replacement of standardized 240 minutes acquisition in PD patients, but this result is not confirmed in HF patients, in which the acquisition at 240 min is confirmed as the most affordable timing for image interpretation, emphasizing the different pathophysiology that underlies these two pathologies.

Background: New treatments combating bone and extraskeletal metastases are needed for patients with metastatic castration-resistant prostate cancer. The majority of metastases overexpress prostate-specific membrane antigen (PSMA), making it an ideal candidate for targeted radionuclide therapy. Objective: The aim of this study was to test a novel liquid 224Ra/212Pb-generator for the rapid preparation of a dual-alpha targeting solution. Here, PSMA-targeting ligands are labelled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, natural bone-seeking 224Ra targeting sclerotic bone metastases and 212Pb-chelated PSMA ligands targeting PSMA-expressing tumour cells are obtained. Methods: Two PSMA-targeting ligands, the p-SCN-Bn-TCMC-PSMA ligand (NG001), specifically developed for chelating 212Pb, and the most clinically used DOTA-based PSMA-617 were labelled with 212Pb. Radiolabelling and targeting potential were investigated in situ, in vitro (PSMA-positive C4-2 human prostate cancer cells) and in vivo (athymic mice bearing C4-2 xenografts). Results: NG001 was rapidly labelled with 212Pb (radiochemical purity >94% at concentrations of ≥15 μg/ml) using the liquid 224Ra/212Pb-generator. The high radiochemical purity and stability of [212Pb]Pb- NG001 were demonstrated over 48 hours in the presence of ascorbic acid and albumin. Similar binding abilities of the 212Pb-labelled ligands were observed in C4-2 cells. The PSMA ligands displayed comparable tumour uptake after 2 hours, but NG001 showed a 3.5-fold lower kidney uptake than PSMA- 617. Radium-224 was not chelated and, hence, showed high uptake in bones. Conclusion: A fast method for the labelling of PSMA ligands with 212Pb in the 224Ra/212Pb-solution was developed. Thus, further in vivo studies with dual tumour targeting by alpha-particles are warranted.

Purpose: 99mTc-HMPAO radiolabeled autologous leukocyte scintigraphy is routinely used clinically for infection imaging. Leukocytes are mostly separated via sedimentation. It is unknown whether leukocytes are clearly separated by sedimentation or selectively labeled. Therefore, in this study, the blood cell numbers were investigated after leukocyte radiolabeling to identify the cells strongly radiolabeled by 99mTc-HMPAO. Methods: This study was performed with leftover blood samples of the patients who underwent 99mTc-HMPAO scintigraphy at Chonbuk National University Hospital (2018-2019). The blood of 22 patients was drawn for 99mTc-HMPAO scintigraphy. WBCs were separated via conventional sedimentation at our clinic and radiolabeled. The concentration of cell components was determined using an automatic hematology analyzer. The cells in the final sample injectate sample were separated using Histopaque and counted with a dose calibrator. Results: The average numbers of RBCs, WBCs, and PLTs in the final injection sample were 79 ± 33, 23.26 ± 11.95, and 229.5 ± 206.57 x 103/μL, respectively. The PLT number was almost 10-fold the number of WBCs. The number of RBCs was nearly 3-fold higher than WBCs [RBC/WBC ratio = 4.67 ± 3.58, and PLT/WBC ratio = 10.65 ± 12.46]. Following Histopaque separation, the activity of each layer showed 99mTc-HMPAO labeling of WBC > RBC > PLT in order. The total activity/cell numbers of WBCs, RBCs and PLTs were 0.016 ± 0.010, 0.005 ± 0.005 and 0.003 ± 0.002, respectively (p > 0.05). Conclusion: Although the numbers of RBCs and PLTs were highly increased after sedimentation, their individual cellular activity was lower than that of WBCs. 99mTc-HMPAO was more selective to WBCs than RBCs or PLTs. In conclusion, a higher number of WBCs were radiolabeled compared with RBCs and PLTs.

Objective: The aim of this study was to develop 99mTc-[HYNIC-X-D-Phe13]-BBN(7-14)NH2 derivatives using two different tripeptidic spacer groups (X=GGG and X=SSS) in order to improve its pharmacokinetics, in vitro stability, specific binding, and affinity. Background: Bombesin (BBN), a 14-aminoacid amphibian peptide homolog of mammalian gastrinreleasing peptide (GRP), has demonstrated the ability to bind with high affinity and specificity to GRP receptor, which is overexpressed on a variety of human cancers. Methods: Peptide conjugates labeled with 99mTc using tricine-EDDA and radiochemical purity was assessed by TLC and HPLC. The stability of radio conjugates was evaluated in the presence of saline and human serum. Affinity, internalization, and also dissociation Constant was evaluated using MDAMB- 231 and PC-3 cell line. Biodistribution study was performed in BALB/C mice. Results: Labeling yield of >95% was obtained. The change introduced in the BBN sequence increased plasma stability. In vitro blocking studies showed that binding and internalization of both radiolabeled peptides are mediated by their receptors on the surface of MDA-MB-231 and PC-3 cells. Biodistribution results demonstrated a rapid blood clearance, with predominantly renal excretion. Specific binding in GRP receptor-positive tissues, such as pancreas was confirmed with a blocking study. Conclusion: The introduction of the spacer sequence between chelator and BBN(7-14) led to improved bidistribution. Analog with tri-Gly spacer is the more promising radiopeptide for targeting GRP receptors than Ser conjugates. Therefore, Therefore, these analogs can be considered as a candidate for the identification of bombesin-positive tumors.

Background: To our knowledge, no previous study or literature review has been performed about the effects of the extravasation of therapeutic radiopharmaceutical agents and its potential consequences, especially regarding alpha-particle emitting radiopharmaceuticals. Methods: Even if Radium-223 dichloride is known to be a relatively safe drug to manage, despite the correctness of the procedures applied , unexpected delayed adverse effects can occur. In our vast experience, we rarely observed lymphedema, even after some time, at the site of administration. Results: Management of lymphedema caused by radiopharmaceuticals administration has been addressed through clinical examples. The sudden intervention allowed a fast remission of the signs and symptoms complained by patients treated with Radium-223 dichloride. Conclusion: The management of adverse effects after radiopharmaceuticals administration as in case of lymphedema onset, is extremely simple. These data confirm the safety of Radium-223 treatment.