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[en] Over recent years, within the community of radiopharmaceutical sciences, there has been an increased incidence of incorrect usage of established scientific terms and conventions, and even the emergence of ‘self-invented’ terms. Here, in order to address these concerns, an international Working Group on ‘Nomenclature in Radiopharmaceutical Chemistry and related areas’ was established in 2015 to achieve clarification of terms and to generate consensus on the utilisation of a standardised nomenclature pertinent to the field. Upon open consultation, the following consensus guidelines were agreed, which aim to: Provide a reference source for nomenclature good practice in the radiopharma-ceutical sciences; Clarify the use of terms and rules concerning exclusively radiopharmaceutical terminology, i.e. nuclear- and radiochemical terms, symbols and expressions; Address gaps and inconsistencies in existing radiochemistry nomenclature rules; Provide source literature for further harmonisation beyond our immediate peer group (publishers, editors, IUPAC, pharmacopoeias, etc.).
[en] Scandium-44 g (half-life 3.97 h) shows promise for application in positron emission tomography (PET), due to favorable decay parameters. One of the sources of "4"4"gSc is the "4"4Ti/"4"4"gSc generator, which can conveniently provide this radioisotope on a daily basis at a diagnostic facility. Titanium-44 (half-life 60.0 a), in turn, can be obtained via proton irradiation of scandium metal targets. A substantial "4"4Ti product batch, however, requires high beam currents, long irradiation times and an elaborate chemical procedure for "4"4Ti isolation and purification. This study describes the production of a combined 175 MBq (4.7 mCi) batch yield of "4"4Ti in week long proton irradiations at the Los Alamos Isotope Production Facility (LANL-IPF) and the Brookhaven Linac Isotope Producer (BNL-BLIP). A two-step ion exchange chromatography based chemical separation method is introduced: first, a coarse separation of "4"4Ti via anion exchange sorption in concentrated HCl results in a "4"4Tc/Sc separation factor of 10"2–10"3. A second, cation exchange based step in HCl media is then applied for "4"4Ti fine purification from residual Sc mass. In conclusion, this method yields a 90–97% "4"4Ti recovery with an overall Ti/Sc separation factor of ≥10"6.
[en] Trithiol chelates are suitable for labeling radioarsenic (72As: 2.49 MeV β+, 26 h; 77As: 0.683 MeV β-, 38.8 h) to form potential theranostic radiopharmaceuticals for PET imaging and therapy. In this paper, to investigate the in vivo stability of trithiol chelates complexed with no carrier added (nca) radioarsenic, a bifunctional trithiol chelate was developed, and conjugated to bombesin(7–14)NH2 as a model peptide. A trithiol-BBN(7–14)NH2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol-BBN(7–14)NH2 conjugate was radiolabeled with 77As, its in vitro stability assessed, and biodistribution studies were performed in CF-1 normal mice of free [77As]arsenate and 77As-trithiol- BBN(7–14)NH2. The trithiol-BBN(7–14)NH2 conjugate, its precursors and its As-trithiol-BBN(7–14)NH2 complex were fully characterized. Radiolabeling studies with nca 77As resulted in over 90% radiochemical yield of 77As-trithiol-BBN, which was stable for over 48 h. Biodistribution studies were performed with both free [77As]arsenate and Sep-Pak® purified 77As-trithiol-BBN(7–14)NH2. Compared to the fast renal clearance of free [77As]arsenate, 77As-trithiol-BBN(7–14)NH2 demonstrated increased retention with clearance mainly through the hepatobiliary system, consistent with the lipophilicity of the 77As-trithiol-BBN(714)NH2 complex. Finally, the combined in vitro stability of 77As-trithiol-BBN(7–14)NH2 and the biodistribution results demonstrate its high in vivo stability, making the trithiol a promising platform for developing radioarsenic-based theranostic radiopharmaceuticals.
[en] Rhenium-186 g (t_1_/_2 = 3.72 d) is a β– emitting isotope suitable for theranostic applications. Current production methods rely on reactor production by way of the reaction "1"8"5Re(n,γ)"1"8"6"gRe, which results in low specific activities limiting its use for cancer therapy. Production via charged particle activation of enriched "1"8"6W results in a "1"8"6"gRe product with a much specific activity, allowing it to be used more broadly for targeted radiotherapy applications. Furthermore, this targets the unmet clinical need for more efficient radiotherapeutics.
[en] Introduction: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are tumors that can exhibit a malignant behavior. Targeted radiotherapy with 131I-metaiodobenzylguanidine (131I-MIBG) has proven useful in patients with unresectable, metastatic and/or relapsed disease. Methods: We review the literature and our experience at UCSF to highlight important characteristics of PHEO/PGL and the use of 131I-MIBG in the treatment of this disease. Results: These tumors are rare, with a diagnosed incidence of only two to four cases per million annually; 40% are discovered at autopsy. Clinical manifestations are caused by excess secretion of catecholamines, although some PGLs are nonsecretory. Approximately 25% of patients with PHEO/PGLs have an underlying genetic predisposition. The risk of a germline mutation is higher in children. Diagnostic evaluation should include serial determinations of fractionated metanephrines and serum chromogranin A. Staging requires both 123I-MIBG and full-body magnetic resonance imaging or 18FDG-PET scanning. The primary treatment for PHEO/PGL is resection. Patients may be candidates for treatment with 131I-MIBG if they have unresectable or metastatic tumors that are avid for MIBG. Such patients usually respond to this targeted radioisotope therapy and many achieve a durable remission. Myelosuppression is a dose-related side effect that can be treated with transfusions or autologous hematopoietic stem cells. Late side effects can include infertility, myelodysplasia and second cancers. Conclusions: Treatment with 131I-MIBG can be considered for patients if surgery is not feasible. There are significant risks associated with this treatment, but the majority of patients will respond. Treatment with 131I-MIBG should be done at institutions with experience in delivering targeted radiotherapeutics
[en] Introduction: The production of 18F-radiotracers using continuous flow microfluidics is under-utilized due to perceived equipment limitations. We describe the dose-on-demand principle, whereby the back-to-back production of multiple, diverse 18F-radiotracers can be prepared on the same day, on the same microfluidic system using the same batch of [18F]fluoride, the same microreactor, the same HPLC column and SPE cartridge to obtain a useful production yield. Methods: [18F]MEL050, [18F]Fallypride and [18F]PBR111 were radiolabeled with [18F]fluoride using the Advion NanoTek Microfluidic Synthesis System. The outlet of the microreactor was connected to an automated HPLC injector and following the collection of the product, SPE reformulation produced the 18F-radiotracer in <10% ethanolic saline. A thorough automated cleaning procedure was implemented to ensure no cross-contamination between radiotracer synthesis. Results: The complete productions for [18F]MEL050 and [18F]Fallypride were performed at total flow rates of 20 μL/min, resulting in 40 ± 13% and 25 ± 13% RCY respectively. [18F]PBR111 was performed at 200 μL/min to obtain 27 ± 8% RCY. Molar activities for each 18F-radiotracer were >100 GBq/μmol and radiochemical purities were >97%, implying that the cleaning procedure was effective. Conclusions: Using the same initial solution of [18F]fluoride, microreactor, HPLC column and SPE cartridge, three diverse 18F-radiotracers could be produced in yields sufficient for preclinical studies in a back-to-back fashion using a microfluidic system with no detectable cross-contamination.
[en] Neutron-activation is a promising method of generating radiotherapeutics with minimal handling of radioactive materials. Graphene oxide nanoplatelets (GONs) were examined as a carrier for neutron-activatable holmium with the purpose of exploiting inherent characteristics for theranostic application. GONs were hypothesized to be an ideal candidate for this application owing to their desirable characteristics such as a rigid structure, high metal loading capacity, low density, heat resistance, and the ability to withstand harsh environments associated with the neutron-activation process. Non-covalently PEGylated GONs (GONs-PEG) offered enhanced dispersibility and biocompatibility, and also exhibited increased holmium loading capacity nearly two-fold greater than GONs. Holmium leaching was investigated over a wide pH range, including conditions that mimic the tumor microenvironment, following neutron irradiation. The in vitro cell-based cytotoxicity analysis of GONs-based formulations with non-radioactive holmium confirmed their safety profile within cells. The results demonstrate the potential of GONs as a carrier of neutron-activatable radiotherapeutic agents.
[en] Introduction: The commercially available 68Ge/68Ga generators are generally used in clinical context in conjunction with automated or semi-automated modules for the syntheses of 68Ga radiopharmaceuticals. It is desirable to develop strategies for the formulation of 68Ga-radiopharmaceuticals without use of such expensive modules in order to make 68Ga-based clinical positron emission tomography (PET) more popular and affordable worldwide. Methods: An organic matrix based 68Ge/68Ga generator was used for preparation of clinically relevant doses of four different 68Ga-based radiopharmaceuticals, namely 68Ga-DOTA-NOC, 68Ga-NODAGA-RGD2, 68Ga-PSMA-11 and 68Ga-BPAMD. Detailed performance evaluation of the generator was carried out over the period of 9 months. The radiolabeling conditions were optimized in a hospital radiopharmacy directly utilizing 68Ga eluted from the generator without use of any synthesis module. Quality control tests of the radiopharmaceuticals were carried out to assess their suitability for clinical use. The clinical utility of the synthesized radiopharmaceuticals was ascertained by performing PET scans in human patients. Results: During the period of evaluation, 68Ga could be obtained from the generator in 4 mL of 0.05 M HCl with 60–85% elution yield and >99.99% radionuclidic purity. While directly using 68Ga eluted from the generator, the 68Ga-based radiopharmaceuticals could be prepared with >95% radiochemical purity and they met all the requirements for clinical administration. The clinical efficacy of the radiopharmaceuticals synthesized was established by PET scans in human patients. The performance of the generator remained consistent over the 9-month period and >100 clinical doses of different radiopharmaceuticals were prepared with excellent reproducibility and clinical effectiveness. Conclusions: The promising results obtained in this study would make 68Ga-radiopharmacy more practical and cost effective in clinical context. To the best of our knowledge, this is the first report on the clinical scale syntheses and utilization of 68Ga-based radiopharmaceuticals without using any synthesis module.
[en] Introduction: Due to the rise in the number of patients with dementia the imperative for finding new diagnostic and treatment options becomes ever more pressing. While significant progress has been made in PET imaging of Aβ aggregates both in vitro and in vivo, options for imaging tau protein aggregates selectively are still limited. Based on the work previously published by researchers from the Tohoku University, Japan, that resulted in the development of [18F]THK-5351, we have undertaken an effort to develop a carbon-11 version of the identical structure - [11C]THK-5351. In parallel, THK-5351 was also labeled with tritium ([3H]THK-5351) for use in in vitro autoradiography (ARG). Methods: The carbon-11 labeling was performed starting with di-protected enantiomeric pure precursor - tert-butyl 5-(6-((2S)-3-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)propoxy)quinolin-2-yl) pyridin-2-yl carbamate, which was reacted with [11C]MeI, using DMF as the solvent and NaH as base, followed by deprotection with trifluoroacetic acid/water mixture, resulting in enantiomerically pure carbon-11 radioligand, [11C]THK-5351 - (S)-1-fluoro-3-(2-(6-([11C]methylamino)pyridin-3-yl)quinolin-6-yloxy) propan-2-ol. Tritium labeling and purification of [3H]THK-5351 were undertaken using similar approach, resulting in [3H]THK-5351 with RCP >99.8% and specific radioactivity of 1.3 GBq/μmol. Results: [11C]THK-5351 was produced in good yield (1900 ± 355 MBq), specific radioactivity (SRA) (361 ± 119 GBq/μmol at EOS + 20 min) and radiochemical purity (RCP) (>99.8%), with enantiomeric purity of 98.7%. [3H]THK-5351 was evaluated for ARG of tau binding in post-mortem human brain tissue using cortical sections from one AD patient and one control subject. [3H]THK-5351 binding density was higher in the AD patient compared to the control subject, the binding was displaced by unlabeled THK-5351 confirming specific [3H]THK-5351 binding.
[en] Radioimmuno-conjugated (Rhenium-188 labeled Rituximab), 3-aminopropyltriethoxysilane (APTES)-polyethylene glycol (PEG) coated iron oxide nanoparticles were synthesized and then characterized. Therapeutic effect and targeting efficacy of complex were evaluated in CD20 express B cell lines and tumor bearing Balb/c mice respectively. To reach these purposes, superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized using coprecipitation method and then their surface was treated with APTES for increasing retention time of SPIONs in blood circulation and amine group creation. In the next step, N-hydroxysuccinimide (NHS) ester of polyethylene glycol maleimide (NHS-PEG-Mal) was conjugated to the APTES-treated SPIONs. After radiolabeling of Rituximab antibody with Rhenium-188 (T1/2 = 16.9 h) using synthesized N2S4 chelator, it was attached to the APTES-PEG-MAL-SPIONs surface through thiol-maleimide coupling reaction. In vitro evaluation of the 188ReN2S4-Rituximab-SPION-complex thus obtained revealed that at 24 and 48 h post-treatment effective cancer cell killing had been achieved. Bio-distribution study in tumor bearing mice showed capability of this complex for targeted cancer therapy. Active and passive tumor targeting strategies were applied through incorporated anti-CD20 (Rituximab) antibody and also enhanced permeability and retention (EPR) effect of solid tumors for nanoparticles respectively.