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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] Introduction: Neuroinflammation is associated with several neurological disorders, including Alzheimer's disease (AD). The translocator protein 18 kDa (TSPO), due to its overexpression during microglial activation and relatively low levels in the brain under normal neurophysiological conditions, is commonly used as an in vivo biomarker for neuroinflammation. Reported here is the preclinical evaluation of [F-18]F-DPA, a promising new TSPO-specific radioligand, as a tool for the detection of activated microglia at different ages in the APP/PS1-21 mouse model of AD and a blocking study to determine the specificity of the tracer. Methods: [F-18]F-DPA was synthesised by the previously reported electrophilic F-18-fluorination methodology. In vivo PET and ex vivo brain autoradiography were used to observe the tracer distribution in the brains of APP/PS1-21 and wild type mice at different ages (4.5-24 months). The biodistribution and degree of metabolism of [F-18]F-DPA were analysed and the specificity of [F-18]F-DPA for its target was determined by pre-treatment with PK11195. Results: The in vivo PET imaging and ex vivo brain autoradiography data showed that [F-18]F-DPA uptake in the brains of the transgenic animals increased with age, however, there was a drop in the tracer uptake at 19 mo. Despite the slight increase in [F-18]F-DPA uptake with age in healthy animal brains, significant differences between wild type and transgenic animals were seen in vivo at 9 months and ex vivo already at 4.5 months. The specificity study demonstrated that PK11195 can be used to significantly block [F-18]F-DPA uptake in all the brain regions studied. Conclusions: In vivo time activity curves plateaued at approximately 20-40 min suggesting that this is the optimal imaging time. Significant differences in vivo are seen at 9 and 12 mo. Due to the higher resolution, ex vivo autoradiography with [F-18]F-DPA can be used to visualise activated microglia at an early stage of AD pathology. (authors)
[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] The majority of pheochromocytomas and paragangliomas are benign, with malignancy occurring in approximately 10% of pheochromocytoma patients. The malignancy rate among paragangliomas is 15-35% or higher if associated with succinate dehydrogenase B gene mutations. The 5-year mortality rate in malignant pheochromocytoma and paraganglioma is nearly 50%. Malignancy of both pheochromocytoma and paraganglioma is determined by the existence of metastasis or local invasion and not by the cellular characteristics. There are no known clinical, biochemical or histopathological differences between pheochromocytoma and paraganglioma. Metaiodobenzylguanidine (MIBG) radiolabeled with either 123I or 131I has been used to diagnose neuroendocrine tumors such as paraganglioma and pheochromocytoma, and 131I-MIBG has been used to treat these tumors. The role of radioiodinated MIBG in treating neuroendocrine tumors is still being evaluated. More recently, no-carrier-added (nca) MIBG has become available, and the advantages of nca MIBG over ca MIBG are being demonstrated. This article reviews the biology of paragangliomas and pheochromocytomas, the role of MIBG imaging in the diagnosis of these tumors and the role of both ca and nca 131I-MIBG in the treatment of these tumors. New data on nca 131I-MIBG in the therapy of these tumors are included
[en] Introduction: In recent years extra-corporal application of boron neutron capture therapy (BNCT) was evaluated for liver primary tumors or liver metastases. A prerequisite for such a high-risk procedure is proof of preferential delivery and high uptake of a 10B-pharmaceutical in liver malignancies. In this work we evaluated in a preclinical tumor model if [18F]FBPA tissue distribution measured with PET is able to predict the tissue distribution of [10B]L-BPA. Methods: Tumor bearing mice (hepatocellular carcinoma cell line, HuH-7) were either subject of a [18F]FBPA-PET scan with subsequent measurement of radioactivity content in extracted organs using a gamma counter or injected with [10B]L-BPA with tissue samples analyzed by prompt gamma activation analysis (PGAA) or quantitative neutron capture radiography (QNCR). The impact of L-tyrosine, L-DOPA and L-BPA preloading on the tissue distribution of [18F]FBPA and [10B]L-BPA was evaluated and the pharmacokinetics of [18F]FBPA investigated by compartment modeling. Results: We found a significant correlation between [18F]FBPA and [10B]L-BPA uptake in tumors and various organs as well as high accumulation levels in pancreas and kidneys as reported in previous studies. Tumor-to-liver ratios of [18F]FBPA ranged from 1.2 to 1.5. Preloading did not increase the uptake of [18F]FBPA or [10B]L-BPA in any organ and compartment modeling showed no statistically significant differences in [18F]FBPA tumor kinetics. Conclusions: [18F]FBPA-PET predicts [10B]L-BPA concentration after amino acid preloading in HuH-7 hepatocellular carcinoma models. Preloading had no effect on tumor uptake of [18F]FBPA. Advances in knowledge: Despite differences in chemical structure and administered dose [18F]FBPA and [10B]L-BPA demonstrate an equivalent biodistribution in a preclinical tumor model. Implications for patient care: [18F]FBPA-PET is suitable for treatment planning and dose calculations in BNCT applications for liver malignancies. However, alternative tracers with more favorable tumor-to-liver ratios should be investigated.
[en] Introduction: Peripheral artery disease can lead to severe disability and limb loss. Therapeutic strategies focussing on macrovascular repair have shown benefit but have not significantly reduced amputation rates in progressive PAD. Proangiogenic small molecule therapies may substantially improve vascularisation in limb ischemia. The purpose of the current study was to assess the proangiogenic effects of simvastatin in a murine model of hind limb ischemia using longitudinal multimodal imaging. Methods: Mice underwent surgical intervention to induce hind limb ischemia, and were treated with simvastatin orally for 28 days. Neovascularisation was assessed using 99mTc-RGD SPECT imaging, and macrovascular volume was assessed by quantitative time of flight MRI. At each imaging time point, VEGF expression and capillary vessel density were quantified using immunohistochemical analysis. Results: Simvastatin significantly increased 99mTc-RGD retention in the ischemic hind limb by day 3 post-surgery, with maximal retention at day 8. Vascular volume was significantly increased in the ischemic hind limb of simvastatin treated animals, but only by day 22. Immunohistochemical analysis shows that simvastatin significantly augmented tissue VEGF expression from day 8 with increase in capillary density (CD31+) from day 14. Conclusions: Early assessment of proangiogenic therapy efficacy can be identified using 99mTc-RGD SPECT, which displays significant increases in retention before macrovascular volume changes are measureable with MRI. Advances in knowledge and implications for patient care: Simvastatin offers an effective proangiogenic therapy as an adjunct for management of limb ischemia. Simvastatin induces integrin expression and vascular remodeling leading to neovascularisation and improved perfusion.
[en] Introduction: Technetium-99m-hexamethylpropyleneamine oxime (99mTc-HMPAO) is potentially useful for the assessment of cerebral blood flow (CBF) in small animals. In this paper, a procedure for quantitation of rat CBF using 99mTc-HMPAO was determined. Methods: Biodistribution of 99mTc-radioactivity in normal rats was determined after intravenous administration of 99mTc-HMPAO. Acetazolamide treated rats were intravenously administered with the mixture of 99mTc-HMPAO and N-isopropyl-[125I]iodoamphetamine ([125I]IMP), and arterial blood was then collected for 5 min. After blood sampling, the brain radioactivity concentration was measured with the auto-well γ counter. Results: The brain radioactivity concentration after intravenous administration of 99mTc-HMPAO was steady from 14 s to 60 min post-injection. A double tracer experiment using 99mTc-HMPAO and [125I]IMP showed that 19 s was the average of the optimal integration interval of arterial blood 99mTc-radioactivity concentration to obtain CBF values measured by 99mTc-HMPAO identical to those determined by [125I]IMP. The CBF value determined by 99mTc-HMPAO, calculated by dividing the brain radioactivity concentration at 5 min post-injection by the integrated arterial blood radioactivity concentration until 19 s post-injection, was well correlated with CBF as determined by [125I]IMP. Conclusion: These results suggest that the CBF quantitation procedure described in this paper could be useful for rat CBF assessment.
[en] Background: Prostate-specific membrane antigen (PSMA) is highly over-expressed in advanced prostate cancers. 68Ga-labeled PSMA inhibitors (iPSMA) are currently used for prostate cancer detection by PET imaging. The availability of simple, efficient and reproducible radiolabeling procedures is essential for developing new SPECT radiopharmaceuticals for clinical translation. The aim of this research was to prepare 99mTc-EDDA/HYNIC-Lys(Nal)-Urea-Glu (99mTc-EDDA/HYNIC-iPSMA) obtained from lyophilized kit formulations and evaluate the in vitro and in vivo radiopharmaceutical binding to prostate cancer cells over-expressing PSMA, as well as the 99mTc-EDDA/HYNIC-iPSMA normal biodistribution in humans and the preliminary uptake in patients with prostate cancer. Methods: 99mTc labeling was performed by adding sodium pertechnetate solution and a 0.2 M phosphate buffer (pH 7.0) to a lyophilized formulation containing HYNIC-iPSMA, EDDA, tricine, mannitol and stannous chloride. The radiochemical purity was evaluated by reversed-phase HPLC and ITLC-SG analyses. Stability studies in human serum were performed by size-exclusion HPLC. In vitro cell uptake was tested using prostate cancer cells (LNCaP) with blocked and non-blocked receptors. Biodistribution and tumor uptake were determined in LNCaP tumor-bearing nude mice with blocked and non-blocked receptors, and images were obtained using a micro-SPECT/CT. Whole-body images from three healthy men and two patients with histologically-confirmed prostate cancer (one of them with a previous 68Ga-PSMA-617scan) were acquired at 1 h and 3 h after 99mTc-EDDA/HYNIC-iPSMA administration with radiochemical purities of >98%. Results: In vitro and in vivo studies showed high radiopharmaceutical stability in human serum, specific recognition for PSMA, high tumor uptake (10.22 ± 2.96% ID/g at 1 h) with rapid blood clearance and mainly kidney elimination. Preliminary images in patients demonstrated the ability of 99mTc-EDDA/HYNIC-iPSMA to detect tumors and metastases of prostate cancer as well as 68Ga-PSMA-617 does. Conclusions: The results obtained in this study warrant further dosimetry and clinical studies to determine the specificity and sensitivity of 99mTc-EDDA/HYNIC-iPSMA.