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The favorable decay characteristics of 161 Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). 161 Tb decays with a similar half-life to 177 Lu, but beyond the emission of β - -particles and γ-rays, 161 Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of 161 Tb and 177 Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake. Methods: [ 161 Tb]Tb-SibuDAB and [ 161 Tb]Tb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor-bearing mice. The 177 Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. Results: The prostate-specific membrane antigen (PSMA)-targeting radioligands, irrespective of whether labeled with 161 Tb or 177 Lu, showed similar in vitro data and comparable tissue distribution profiles. As a result of the albumin-binding properties, [ 161 Tb]Tb/[ 177 Lu]Lu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%-69% injected activity per gram at 24 h after injection) than [ 161 Tb]Tb/[ 177 Lu]Lu-PSMA-I&T (30%-35% injected activity per gram at 24 h after injection). [ 161 Tb]Tb-SibuDAB inhibited tumor growth more effectively than [ 161 Tb]Tb-PSMA-I&T, as can be ascribed to its 4-fold increased absorbed tumor dose. At any of the applied activities, the 161 Tb-based radioligands were therapeutically more effective than their 177 Lu-labeled counterparts, as agreed with the approximately 40% increased tumor dose of 161 Tb compared with that of 177 Lu. Under the given experimental conditions, no obvious adverse events were observed. Conclusion: The data of this study indicate the promising potential of 161 Tb in combination with SibuDAB for RLT of prostate cancer. Future clinical studies using 161 Tb-based RLT will shed light on a potential clinical benefit of 161 Tb over 177 Lu., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

161 Tb is an interesting radionuclide for application in the treatment of neuroendocrine neoplasms' small metastases and single cancer cells because of its conversion and Auger-electron emission. Tb has coordination chemistry similar to that of Lu; therefore, like 177 Lu, it can stably radiolabel DOTATOC, one of the leading peptides used for the treatment of neuroendocrine neoplasms. However, 161 Tb is a recently developed radionuclide that has not yet been specified for clinical use. Therefore, the aim of the current work was to characterize and specify 161 Tb and to develop a protocol for the synthesis and quality control of 161 Tb-DOTATOC with a fully automated process conforming to good-manufacturing-practice guidelines, in view of its clinical use. Methods: 161 Tb, produced by neutron irradiation of 160 Gd in high-flux reactors followed by radiochemical separation from its target material, was characterized regarding its radionuclidic purity, chemical purity, endotoxin level, and radiochemical purity (RCP) in analogy to what is described in the European Pharmacopoeia for no-carrier-added 177 Lu. In addition, 161 Tb was introduced into a fully automated cassette-module synthesis to produce 161 Tb-DOTATOC, as used for 177 Lu-DOTATOC. The quality and stability of the produced radiopharmaceutical in terms of identity, RCP, and ethanol and endotoxin content were assessed by means of high-performance liquid chromatography, gas chromatography, and an endotoxin test, respectively. Results: 161 Tb produced under the described conditions showed, as the no-carrier-added 177 Lu, a pH of 1-2, radionuclidic purity and RCP of more than 99.9%, and an endotoxin level below the permitted range (175 IU/mL), indicating its appropriate quality for clinical use. In addition, an efficient and robust procedure for the automated production and quality control of 161 Tb-DOTATOC with clinically applicable specifications and activity levels, that is, 1.0-7.4 GBq in 20 mL, was developed. The radiopharmaceutical's quality control was also developed using chromatographic methods, which confirmed the product's stability (RCP ≥ 95%) over 24 h. Conclusion: The current study demonstrated that 161 Tb has appropriate features for clinical use. The developed synthesis protocol guarantees high yields and safe preparation of injectable 161 Tb-DOTATOC. The investigated approach could be translated to other DOTA-derivatized peptides; thus, 161 Tb could be successfully applied in clinical practice for radionuclide therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

161 Tb has decay properties similar to those of 177 Lu but, additionally, emits a substantial number of conversion and Auger electrons. The aim of this study was to apply 161 Tb in a clinical setting and to investigate the feasibility of visualizing the physiologic and tumor biodistributions of 161 Tb-DOTATOC. Methods: 161 Tb was shipped from Paul Scherrer Institute, Villigen-PSI, Switzerland, to Zentralklinik Bad Berka, Bad Berka, Germany, where it was used for the radiolabeling of DOTATOC. In 2 separate studies, 596 and 1,300 MBq of 161 Tb-DOTATOC were administered to a 35-y-old male patient with a metastatic, well-differentiated, nonfunctional malignant paraganglioma and a 70-y-old male patient with a metastatic, functional neuroendocrine neoplasm of the pancreatic tail, respectively. Whole-body planar γ-scintigraphy images were acquired over a period of several days for dosimetry calculations. SPECT/CT images were reconstructed using a recently established protocol and visually analyzed. Patients were observed for adverse events after the application of 161 Tb-DOTATOC. Results: The radiolabeling of DOTATOC with 161 Tb was readily achieved with a high radiochemical purity suitable for patient application. Planar images and dosimetry provided the expected time-dependent biodistribution of 161 Tb-DOTATOC in the liver, kidneys, spleen, and urinary bladder. SPECT/CT images were of high quality and visualized even small metastases in bones and liver. The application of 161 Tb-DOTATOC was well tolerated, and no related adverse events were reported. Conclusion: This study demonstrated the feasibility of imaging even small metastases after the injection of relatively low activities of 161 Tb-DOTATOC using γ-scintigraphy and SPECT/CT. On the basis of this essential first step in translating 161 Tb to clinics, further efforts will be directed toward the application of 161 Tb for therapeutic purposes., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The intense accumulation of prostate-specific membrane antigen (PSMA) radioligands in salivary glands is still not well understood. It is of concern for therapeutic applications of PSMA radioligands, because therapeutic radiation will damage these glands. A better understanding of the uptake mechanism is, therefore, crucial to find solutions to reduce toxicity. The aim of this study was to investigate whether the accumulation of PSMA-targeting radioligands in submandibular glands (SMGs) can be explained with PSMA expression levels using autoradiography (ARG) and immunohistochemistry (IHC). Methods: All patients gave written informed consent for further utility of the biologic material. The SMG of 9 patients, pancreatic tissue of 4 patients, and prostate cancer (PCA) lesions of 9 patients were analyzed. Tissue specimens were analyzed by means of PSMA-IHC (using an anti-PSMA-antibody and an immunoreactivity score system [IRS]) and ARG using 177 Lu-PSMA-617 (with quantification of the relative signal intensity compared with a PSMA-positive standard). The SUV max in salivary glands, pancreas, and PCA tissues were quantified in 60 clinical 68 Ga-PSMA-11 PET scans for recurrent disease as well as the 9 primary tumors selected for ARG and IHC. Results: PCA tissue samples revealed a wide range of PSMA staining intensity on IHC (IRS = 70-300) as well as in ARG (1.3%-22% of standard). This variability on PCA tissue could also be observed in 68 Ga-PSMA-11 PET (SUV max , 4.4-16) with a significant correlation between ARG and SUV max ( P < 0.001, R 2 = 0.897). On IHC, ARG, and 68 Ga-PSMA-11 PET, the pancreatic tissue was negative (IRS = 0, ARG = 0.1% ± 0.05%, SUV max of 3.1 ± 1.1). The SMG tissue displayed only focal expression of PSMA limited to the intercalated ducts on IHC (IRS = 10-15) and a minimal signal on ARG (1.3% ± 0.9%). In contrast, all SMG showed a high 68 Ga-PSMA-11 accumulation on PET scans (SUV max 23.5 ± 5.2). Conclusion: Our results indicate that the high accumulation of PSMA radioligands in salivary glands does not correspond to high PSMA expression levels determined using ARG and IHC. These findings provide evidence, that the significant accumulation of PSMA radioligands in SMG is not primarily a result of PSMA-mediated uptake., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

The aim of this study was to develop the radiosyntheses of diastereomerically pure 6 R - and 6 S -3'-aza-2'- 18 F-fluoro-5-methyltetrahydrofolate (MTHF) (6 R - 18 F- 1 and 6 S - 18 F- 1 ) using the integrated approach and to compare the in vitro and in vivo performance characteristics of both radioligands with the previously reported 3'-aza-2'- 18 F-fluorofolic acid tracer ( 18 F- 2 ), the oxidized form. Methods: 6 R - 18 F- 1, 6 S - 18 F- 1, and 18 F- 2 were radiolabeled with 18 F using aromatic nucleophilic substitution reaction. In vitro cell uptake studies and binding affinity assays were performed using folate receptor (FR)-α-expressing KB cells. PET/CT imaging and biodistribution experiments were performed with KB tumor-bearing mice. Results: Reference compounds 6 R - 1 and 6 S - 1 were obtained after acidic hydrolysis of the corresponding protected intermediates 6 R - 3 and 6 S - 3 in high chemical yields (81%-87%) and chemical purities of more than 95%. 6 R - 18 F- 1, 6 S - 18 F- 1, and 18 F- 2 were obtained after a 2-step radiosynthetic procedure in a decay-corrected radiochemical yield of up to 5% and molar radioactivities ranging from 20 to 250 GBq/μmol. In vitro binding affinity studies using FR-α-positive KB cells gave half-maximal inhibitory concentrations of 27.1 ± 3.7 and 23.8 ± 4.0 nM for 6 R - 1 and 6 S - 1, respectively, which were higher than for the previously reported 3'-aza-2'-fluorofolic acid 2 (1.4 ± 0.5 nM). Comparably high cell uptake values in FR-α-expressing KB cells were found for all 3 radiofolates. In biodistribution studies, exceptionally high KB tumor uptake value of over 32% injected activity per gram of tissue for both 6 R - 18 F- 1 and 6 S - 18 F- 1 was observed at 180 min after injection, whereas for 18 F- 2 only 15% injected activity per gram was found in the KB tumors. Radioactivity uptake in the kidneys, liver, salivary glands, and spleen was substantially different for the 6 R - and 6 S -diastereoisomers and 18 F- 2 Excellent KB tumor visualization was found in PET/CT images with 6 R - 18 F- 1 and 6 S - 18 F- 1, both of which outperformed the corresponding oxidized 18 F- 2. Conclusion: We have successfully radiolabeled 6 R - and 6 S -3'-aza-2'- 18 F-fluoro-5-MTHF with 18 F using the integrated approach. Our results suggest that both 6 R - and 6 S -3'-aza-2'- 18 F-fluoro-5-MTHF are promising reduced radiofolates for imaging FR-α-expressing cancers., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

In recent years, new α-particle-, β - -particle-, and Auger electron-emitting radiometals-such as 67 Cu, 47 Sc, 166 Ho, 161 Tb, 149 Tb, 212 Pb/ 212 Bi, 225 Ac, and 213 Bi-have been produced and evaluated (pre)clinically for therapeutic purposes. In this short review article, the most important routes of production of these radiometals are critically discussed, as are examples of their application in preclinical and clinical studies., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: The folate receptor (FR) has proven a valuable target for nuclear imaging using folic acid radioconjugates. However, using folate-based radiopharmaceuticals for therapy has long been regarded as an unattainable goal because of their considerable renal accumulation. Herein, we present a novel strategy in which a DOTA-folate conjugate with an albumin-binding entity (cm09) was designed with the aim of prolonging circulation in the blood and therewith potentially improving tumor-to-kidney ratios., Methods: The folate conjugate cm09 was radiolabeled with (177)LuCl(3), and stability experiments were performed in plasma. Cell uptake studies were performed on FR-positive KB tumor cells, and an ultrafiltration assay was used to determine the plasma protein-binding properties of (177)Lu-cm09. In vivo, (177)Lu-cm09 was tested in KB tumor-bearing mice using SPECT/CT. The therapeutic anticancer effect of (177)Lu-cm09 (20 MBq) applied as a single injection or as fractionated injections was investigated in different groups of mice (n = 5) by monitoring tumor size and the survival time of treated mice, compared with untreated controls., Results: Compound cm09 was radiolabeled at a specific activity of 40 MBq/nmol, a radiochemical yield of more than 98%, and a stability of more than 99% over 5 d in plasma. Ultrafiltration revealed significant binding of (177)Lu-cm09 to serum proteins (∼91%) in plasma, compared with folate radioconjugate without an albumin-binding entity. Cell uptake and internalization of (177)Lu-cm09 was FR-specific and comparable to other folate radioconjugates. In vivo studies resulted in high tumor uptake (17.56 percentage injected dose per gram [%ID/g] at 4 h after injection), which was almost completely retained for at least 72 h. Renal accumulation was significantly reduced (28 %ID/g at 4 h after injection), compared with folate conjugates that lack an albumin-binding entity (∼70 %ID/g at 4 h after injection). These circumstances enabled SPECT imaging of excellent quality. Radionuclide therapy (1 × 20 MBq) revealed complete remission of tumors in 4 of 5 cases and a significantly prolonged survival time, compared with untreated controls., Conclusion: The modification of a folate radioconjugate with an albumin-binding entity resulted in a significant increase of the tumor-to-kidney ratio of radioactivity, enabling for the first time, to our knowledge, the preclinical application of folic acid-targeted radionuclide therapy in mice.

Unlabelled: Targeting the folate receptor (alpha-FR) with radiolabeled folates for the noninvasive diagnosis and therapy of alpha-FR-overexpressing neoplastic tissue is of great interest. However, the tumor uptake of folate-based radiotracers was shown to be low compared with the high renal retention of radioactivity attributable to alpha-FR expression in the proximal tubule cells. In order to increase the tumor uptake of radiofolates, we wanted to stimulate alpha-FR expression or transport through coapplication of the antifolates methotrexate (MTX), raltitrexed (RTX), and pemetrexed (PMX)., Methods: (99m)Tc-picolylamine monoacetic acid folate ((99m)Tc-PAMA-folate) was used for these studies. The in vitro experiments with antifolates were performed with alpha-FR-positive KB cancer cells. In vivo experiments were performed with KB tumor-bearing athymic nude mice. In vivo images were acquired with a small-animal SPECT/CT scanner., Results: KB cells incubated with solutions (10 micro mol/L) of MTX, RTX, or PMX for 24 h displayed twice as much (99m)Tc-PAMA-folate uptake as untreated cells. In contrast, KB tumor-bearing mice that received MTX intravenously 24 h before (99m)Tc-PAMA-folate showed significantly lower uptake of the radiofolate in tumors (1.35 +/- 0.33 percentage injected dose per gram of tissue [%ID/g] [mean +/- SD]) and the alpha-FR-positive kidneys (9.35 +/- 1.73 %ID/g) than did control mice (2.33 +/- 0.36 and 18.48 +/- 0.72 %ID/g, respectively, at 4 h after injection). When the antifolate PMX and (99m)Tc-PAMA-folate were injected 1 h apart, the tumor uptake of the radiotracer was unaffected (2.21 +/- 0.34 %ID/g at 4 h after injection), whereas radioactivity in the kidneys was significantly decreased (1.14 +/- 0.18 %ID/g at 4 h after injection). In vivo SPECT/CT studies demonstrated the specific accumulation of (99m)Tc-PAMA-folate in tumors and almost a complete absence of radioactivity in the renal tissue of mice preinjected with PMX., Conclusion: Our data suggest that the preadministration of antifolates improves tumor-to-kidney ratios of radiofolates and opens a "therapeutic window" for folates radiolabeled with particle-emitting nuclides, which could otherwise be nephrotoxic.

Unlabelled: Folic acid was linked regioselectively through its alpha- and gamma-carboxyl groups to 4-fluorobenzylamine (FBA), and the alpha- and gamma-FBA-folate regioisomers were evaluated for their ability to bind to folate receptor-positive cells. The 18F-labeled alpha/gamma-FBA-folate counterpart was examined for in vivo tumor targeting efficiency in nude mice bearing folate receptor-positive tumor cells., Methods: 18F-alpha/gamma-FBA-folate was prepared in a 4-step reaction sequence starting from folic acid. The relative binding affinities of the alpha- and gamma-FBA-folates to the folate receptor with respect to parent folic acid were determined in cultured KB-31 cells (nasopharyngeal epidermal carcinoma cell line) overexpressing the folate receptor using 3H-folic acid. Tumor accumulation of the 18F-labeled alpha/gamma-FBA-folate and 18F-FDG was analyzed in vivo by high-resolution PET. Biodistribution and PET studies were performed under baseline and blockage conditions., Results: The radiochemical yield of the coupling step ranged from 15% to 44%, and the maximum specific radioactivity was 24 GBq/micromol. The in vitro binding affinities of the alpha- and gamma-isomers and folic acid were 71, 62, and 41 nmol/L, respectively. PET revealed heterogeneous uptake of the radioligand, with the highest activity concentrations found in the tumor rim. In contrast, 18F-FDG uptake in a nude mouse bearing KB-31 folate receptor-positive tumors was negligible. Radioligand uptake in tumors at 125 min after injection amounted to 6.56% of the injected dose per gram of tissue (%ID/g) in control animals, whereas radioactivity accumulation in the tumors of folic acid-treated animals was significantly reduced by more than 80%-to 1.07 %ID/g (P = 0.001)., Conclusion: This new 18F-labeled folic acid derivative is a promising tool for PET imaging of folate receptor-positive tumors.