Activity Measurement of 44Sc and Calibration of Activity Measurement Instruments on Production Sites and Clinics.

44Sc is a promising radionuclide for positron emission tomography (PET) in nuclear medicine. As a part of the implementation of a production site for 44Sc, precise knowledge of the activity of the product is necessary. At the Paul Scherrer Institute (PSI) and the University of Bern (UniBE), 44Sc is produced by enriched 44CaO-target irradiation with a cyclotron. The two sites use different techniques for activity measurement, namely a dose calibrator at the PSI and a gamma-ray spectrometry system at UniBE and PSI. In this work, the 44Sc was produced at the PSI, and samples of the product were prepared in dedicated containers for onsite measurements at PSI, UniBE, and the Institute of Radiation Physics (IRA) in Lausanne for precise activity measurement using primary techniques and for the calibration of the reference ionization chambers. An accuracy of 1% was obtained for the activity measurement, allowing for a precise calibration of the dose calibrator and gamma-ray spectrometry of the two production sites. Each production site now has the capability of measuring 44Sc activity with an accuracy of 2%.

Chelation of Theranostic Copper Radioisotopes with S-Rich Macrocycles: From Radiolabelling of Copper-64 to In Vivo Investigation.

Copper radioisotopes are generally employed for cancer imaging and therapy when firmly coordinated via a chelating agent coupled to a tumor-seeking vector. However, the biologically triggered Cu2+-Cu+ redox switching may constrain the in vivo integrity of the resulting complex, leading to demetallation processes. This unsought pathway is expected to be hindered by chelators bearing N, O, and S donors which appropriately complements the borderline-hard and soft nature of Cu2+ and Cu+. In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [64Cu]Cu2+ and the stability of the [64Cu]Cu-complexes thereof were evaluated. Among the chelators considered, the best results were obtained with 1,7-bis [2-(methylsulfanyl)ethyl]-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). DO2A2S was labelled at high molar activities in mild reaction conditions, and its [64Cu]Cu2+ complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [64Cu][Cu(DO2A2S)] revealed a behavior similar to other [64Cu]Cu-labelled cyclen derivatives characterized by high liver and kidney uptake, which could either be ascribed to transchelation phenomena or metabolic processing of the intact complex.

Radiochemical Determination of Long-Lived Radionuclides in Proton-Irradiated Heavy Metal Targets: Part II Tungsten.

In this study, proton-irradiated tungsten targets, up to 2.6 GeV, were investigated for the purpose of the experimental cross-section measurements. Radiochemical separation methods were applied to isolate the residual long-lived alpha-emitters 148Gd, 154Dy, and 146Sm and the beta-emitters 129I and 36Cl from proton-irradiated tungsten targets. The molecular plating technique has been applied to prepare 148Gd, 154Dy, and 146Sm samples for alpha-spectrometry. Production cross-sections of 129I and 36Cl were determined by means of accelerator mass spectrometry. The results are compared with theoretical predictions, obtained with the INCL++-ABLA07 codes, showing good agreement for 36Cl and 148Gd, while a factor of 4 difference was observed for 154Dy, similar to the results obtained for tantalum targets.

A Step-by-Step Guide for the Novel Radiometal Production for Medical Applications: Case Studies with 68Ga, 44Sc, 177Lu and 161Tb.

The production of novel radionuclides is the first step towards the development of new effective radiopharmaceuticals, and the quality thereof directly affects the preclinical and clinical phases. In this review, novel radiometal production for medical applications is briefly elucidated. The production status of the imaging nuclide 44Sc and the therapeutic ß--emitter nuclide 161Tb are compared to their more established counterparts, 68Ga and 177Lu according to their targetry, irradiation process, radiochemistry, and quality control aspects. The detailed discussion of these significant issues will help towards the future introduction of these promising radionuclides into drug manufacture for clinical application under Good Manufacturing Practice (GMP).

Developments toward the Implementation of 44Sc Production at a Medical Cyclotron.

44Sc has favorable properties for cancer diagnosis using Positron Emission Tomography (PET) making it a promising candidate for application in nuclear medicine. The implementation of its production with existing compact medical cyclotrons would mean the next essential milestone in the development of this radionuclide. While the production and application of 44Sc has been comprehensively investigated, the development of specific targetry and irradiation methods is of paramount importance. As a result, the target was optimized for the 44Ca(p,n)44Sc nuclear reaction using CaO instead of CaCO3, ensuring decrease in target radioactive degassing during irradiation and increased radionuclidic yield. Irradiations were performed at the research cyclotron at the Paul Scherrer Institute (~11 MeV, 50 µA, 90 min) and the medical cyclotron at the University of Bern (~13 MeV, 10 µA, 240 min), with yields varying from 200 MBq to 16 GBq. The development of targetry, chemical separation as well as the practical issues and implications of irradiations, are analyzed and discussed. As a proof-of-concept study, the 44Sc produced at the medical cyclotron was used for a preclinical study using a previously developed albumin-binding prostate-specific membrane antigen (PSMA) ligand. This work demonstrates the feasibility to produce 44Sc with high yields and radionuclidic purity using a medical cyclotron, equipped with a commercial solid target station.

Implementation of a new separation method to produce qualitatively improved 64 Cu.

BACKGROUND: 64 Cu (T1/2  = 12.7 h) is an important radionuclide for diagnostic purposes and used for positron emission tomography (PET). A previous method utilized at Paul Scherrer Institute (PSI) proved to be unreliable and, while a method using anion exchange chromatography is a popular choice worldwide, it was felt a different approach was required to obtain a robust chemical separation method. METHODS: Enriched 64 Ni targets were created by electroplating on gold foil. The targets were irradiated with protons degraded to approximately 11 MeV at PSI's Injector 2 72 MeV research cyclotron and subsequently dissolved in HCl. The resultant solution was loaded onto AG MP-50 cation exchange resin and the 64 Cu separated from its target material and radiocobalt impurities, produced as part of the irradiation process, using various specific mixtures of HCl/acetone solution. The eluted product was evaporated and picked up in dilute HCl (0.05 M). The chemical purity of 64 Cu was determined by radiolabeling experiments at the highest possible molar activities. RESULTS: Reproducible results were obtained, yielding 3.6 to 8.3 GBq 64 Cu of high radionuclidic and radiochemical purity. The product was labeled to NODAGA-RGD, achieved at up to 500 MBq/nmol, indicating the high chemical purity. In a proof-of-concept in vivo study, 64 Cu-NODAGA-RGD was used for PET imaging of a tumor-bearing mouse. CONCLUSION: The chemical separation devised to produce high-quality 64 Cu proved to be robust and reproducible. The concept can be used at medical cyclotrons utilizing a solid target station, such that 64 Cu can be used at hospitals for PET imaging.

Radiochemical Determination of Long-Lived Radionuclides in Proton-Irradiated Heavy-Metal Targets: Part I-Tantalum.

In this study, distillation, precipitation, and ion-exchange methods were chosen for the separation of the long-lived ß-emitters 129I, 36Cl and the α-emitters 154Dy, 148Gd, 150Gd, and 146Sm from Ta targets irradiated with protons up to 2.6 GeV to determine their production cross sections. Measurements of 129I/127I and 36Cl/35Cl ratios were performed with accelerator mass spectrometry. After separation of the lanthanides, the molecular plating technique was applied to prepare thin samples to obtain highly resolved α-spectra. Autoradiography and focused ion beam/scanning electron microscopy techniques were used to characterize the lanthanide deposited layer. Experimental cross-section data are compared with theoretical predictions obtained with INCL++ and ABLA07 code, and a satisfactory agreement is observed.

Terbium sisters: current development status and upscaling opportunities.

The interest in terbium radionuclides, which can be used in nuclear medicine, has increased tremendously over the last decade. Several research studies have shown the potential of four terbium radionuclides 149,152,155,161Tb both for cancer diagnosis as well as therapy. The comparison of 161Tb and 177Lu showed 161Tb as the preferred candidate not only for standard radiotherapy, but also for the treatment of minimal residual disease. Nevertheless, among the terbium sisters, currently, only 161Tb has an established production protocol where its no-carrier-added form is obtained via neutron irradiation of enriched 160Gd targets. The other terbium radioisotopes face challenges related to production capacity and production yield, which currently restricts their use in nuclear medicine. The purpose of this review is to report on recent research on the production and separation of terbium sisters and to assess the prospects for upscaling their production for nuclear medicine applications.

The 146 Sm half-life re-measured: consolidating the chronometer for events in the early Solar System.

The half-life of the extinct radiolanthanide 146 Sm , important for both geochronological and astrophysical applications, was re-determined by a combination of mass spectrometry and α -decay counting. Earlier studies provided only limited information on all potential factors that could influence the quantification of the half-life of 146 Sm . Thus, special attention was given  here to a complete documentation of all experimental steps to provide information about any possible artifacts in the data analysis. The half-life of 146 Sm was derived to be 92.0 Ma ± 2.6 Ma, with an uncertainty coverage factor of k = 1 .

Preclinical Evaluation of Gastrin-Releasing Peptide Receptor Antagonists Labeled with 161Tb and 177Lu: A Comparative Study.

To elucidate potential benefits of the Auger-electron-emitting radionuclide 161Tb, we compared the preclinical performance of the gastrin-releasing peptide receptor antagonists RM2 (DOTA-Pip5-d-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) and AMTG (α-Me-Trp8-RM2), each labeled with both 177Lu and 161Tb. Methods: 161Tb/177Lu labeling (90°C, 5 min) and cell-based experiments (PC-3 cells) were performed. In vivo stability (30 min after injection) and biodistribution studies (1-72 h after injection) were performed on PC-3 tumor-bearing CB17-SCID mice. Results: Gastrin-releasing peptide receptor affinity was high for all compounds (half-maximal inhibitory concentration [nM]: [161Tb]Tb-RM2, 2.46 ± 0.16; [161Tb]Tb-AMTG, 2.16 ± 0.09; [177Lu]Lu-RM2, 3.45 ± 0.18; [177Lu]Lu-AMTG, 3.04 ± 0.08), and 75%-84% of cell-associated activity was receptor-bound. In vivo, both AMTG analogs displayed distinctly higher stability (30 min after injection) and noticeably higher tumor retention than their RM2 counterparts. Conclusion: On the basis of preclinical results, [161Tb]Tb-/[177Lu]Lu-AMTG might reveal a higher therapeutic efficacy than [161Tb]Tb-/[177Lu]Lu-RM2, particularly [161Tb]Tb-AMTG because of additional Auger-electron emissions at the cell membrane level.

Determination of the half-life of gadolinium-148.

The half-life of the alpha-emitter 148Gd was measured using the "direct method", in which the number of atoms is directly determined and their activity is then measured. Pure Gd samples containing megabecquerels of 148Gd were obtained by reprocessing proton-irradiated tantalum material. Multicollector-inductively coupled plasma mass spectrometry was performed to determine the amount of 148Gd atoms retrieved. The activity of the 148Gd atoms contained in the Gd sample was measured by means of alpha-spectrometry. The half-life of 148Gd was deduced to be 86.9 years, with a combined uncertainty of 4.5%.

Study of thulium-167 cyclotron production: a potential medically-relevant radionuclide.

Introduction: Targeted Radionuclide Therapy is used for the treatment of tumors in nuclear medicine, while sparing healthy tissues. Its application to cancer treatment is expanding. In particular, Auger-electron emitters potentially exhibit high efficacy in treating either small metastases or single tumor cells due to their short range in tissue. The aim of this paper is to study the feasibility of a large-scale production of thulium-167, an Auger-electron emitter radionuclide, in view of eventual systematic preclinical studies. Methods: Proton-irradiated enriched erbium-167 and erbium-168 oxides were used to measure the production cross sections of thulium-165, thulium-166, thulium-167, and thulium-168 utilizing an 18-MeV medical cyclotron equipped with a Beam Transport Line (BTL) at the Bern medical cyclotron laboratory. The comparison between the experimental and the TENDL 2021 theoretical cross-section results were in good agreement. Additional experiments were performed to assess the production yields of thulium radioisotopes in the BTL. Thulium-167 production yield was also measured irradiating five different target materials (167 Er 2 O 3, 168 Er 2 O 3, nat Tm 2 O 3, nat Yb 2 O 3, 171 Yb 2 O 3) with proton beams up to 63 MeV at the Injector II cyclotron of Paul Scherrer Institute. Results and Discussion: Our experiments showed that an 8-h irradiation of enriched ytterbium-171 oxide produced about 420 MBq of thulium-167 with a radionuclidic purity of 99.95% after 5 days of cooling time with a proton beam of about 53 MeV. Larger activities of thulium-167 can be achieved using enriched erbium-168 oxide with a 23-MeV proton beam, obtaining about 1 GBq after 8-h irradiation with a radionuclidic purity of <99.5% 5 days post end of bombardment.

161Tb-DOTATOC Production Using a Fully Automated Disposable Cassette System: A First Step Toward the Introduction of 161Tb into the Clinic.

161Tb 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 177Lu, it can stably radiolabel DOTATOC, one of the leading peptides used for the treatment of neuroendocrine neoplasms. However, 161Tb 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 161Tb and to develop a protocol for the synthesis and quality control of 161Tb-DOTATOC with a fully automated process conforming to good-manufacturing-practice guidelines, in view of its clinical use. Methods: 161Tb, produced by neutron irradiation of 160Gd 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 177Lu. In addition, 161Tb was introduced into a fully automated cassette-module synthesis to produce 161Tb-DOTATOC, as used for 177Lu-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: 161Tb produced under the described conditions showed, as the no-carrier-added 177Lu, 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 161Tb-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 161Tb has appropriate features for clinical use. The developed synthesis protocol guarantees high yields and safe preparation of injectable 161Tb-DOTATOC. The investigated approach could be translated to other DOTA-derivatized peptides; thus, 161Tb could be successfully applied in clinical practice for radionuclide therapy.

Cross-section measurement of thulium radioisotopes with an 18 MeV medical PET cyclotron for an optimized 165Er production.

165Er is a pure Auger-electron emitter with promising characteristics for therapeutic applications in nuclear medicine. The short penetration path and high Linear Energy Transfer (LET) of the emitted Auger electrons make 165Er particularly suitable for treating small tumor metastases. Several production methods based on the irradiation with charged particles of Er and Ho targets can be found in the literature. In this paper, we report on the study of 165Er indirect production performed via the 166Er(p,2n)165Tm →165Er reaction at the 18 MeV Bern medical cyclotron. Despite the use of highly enriched 166Er2O3 targets, several Tm radioisotopes are produced during the irradiation, making the knowledge of the cross sections involved crucial. For this reason, a precise investigation of the cross sections of the relevant nuclear reactions in the energy range of interest was performed by irradiating Er2O3 targets with different isotopic enrichment levels and using a method based on the inversion of a linear system of equations. For the reactions 164Er(p, γ)165Tm, 166Er(p,n)166Tm, 166Er(p, γ)167Tm, 167Er(p,3n)165Tm, 167Er(p, γ)168Tm, 168Er(p,2n)167Tm and 170Er(p,3n)168Tm, the nuclear cross section was measured for the first time. From the results obtained, the production yield and purity of the parent radioisotope 165Tm were calculated to assess the optimal irradiation conditions. Several production tests with solid targets were performed to confirm these findings.

Novel radionuclides for use in Nuclear Medicine in Europe: where do we stand and where do we go?

BACKGROUND: In order to support the ongoing research across Europe to facilitate access to novel radionuclides, the PRISMAP consortium (European medical radionuclides programme) was established to offer the broadest catalog of non-conventional radionuclides for medical and translational research. The aim of this article is to introduce readers with current status of novel radionuclides in Europe. MAIN BODY: A consortium questionnaire was disseminated through the PRISMAP consortium and user community, professional associations and preclinical/clinical end users in Europe and the current status of clinical end-users in nuclear medicine were identified. A total of 40 preclinical/clinical users institutions took part in the survey. Clinical end users currently use the following radionuclides in their studies: 177Lu, 68 Ga, 111In, 90Y, other alpha emitters, 225Ac, 64Cu and Terbium isotopes. Radionuclides that would be of interest for users within the next 2-5 years are 64Cu, Terbium radionuclide "family" and alpha emitters, such as 225Ac. CONCLUSIONS: Thanks to a questionnaire distributed by the PRISMAP consortium, the current status and needs of clinical end-users in nuclear medicine were identified.

Synthesis and Preclinical Evaluation of Radiolabeled [103Ru]BOLD-100.

The first-in-class ruthenium-based chemotherapeutic agent BOLD-100 (formerly IT-139, NKP-1339, KP1339) is currently the subject of clinical evaluation for the treatment of gastric, pancreatic, colorectal and bile duct cancer. A radiolabeled version of the compound could present a helpful diagnostic tool. Thus, this study investigated the pharmacokinetics of BOLD-100 in more detail to facilitate the stratification of patients for the therapy. The synthesis of [103Ru]BOLD-100, radiolabeled with carrier added (c.a.) ruthenium-103, was established and the product was characterized by HPLC and UV/Vis spectroscopy. In order to compare the radiolabeled and non-radioactive versions of BOLD-100, both complexes were fully evaluated in vitro and in vivo. The cytotoxicity of the compounds was determined in two colon carcinoma cell lines (HCT116 and CT26) and biodistribution studies were performed in Balb/c mice bearing CT26 allografts over a time period of 72 h post injection (p.i.). We report herein preclinical cytotoxicity and pharmacokinetic data for BOLD-100, which were found to be identical to those of its radiolabeled analog [103Ru]BOLD-100.

High precision half-life measurement of the extinct radio-lanthanide Dysprosium-154.

Sixty years after the discovery of 154Dy, the half-life of this pure alpha-emitter was re-measured. 154Dy was radiochemically separated from proton-irradiated tantalum samples. Sector field- and multicollector-inductively coupled plasma mass spectrometry were used to determine the amount of 154Dy retrieved. The disintegration rate of the radio-lanthanide was measured by means of α-spectrometry. The half-life value was determined as (1.40 ± 0.08)∙106 y, with an uncertainty reduced by a factor of ~ 10 compared to the currently adopted value of (3.0 ± 1.5)∙106 y. This precise half-life value is useful for the the correct testing and evaluation of p-process nucleosynthetic models using 154Dy as a seed nucleus or as a reaction product, as well as for the safe disposal of irradiated target material from accelerator driven facilities. As a first application of the half-life value determined in this work, the excitation functions for the production of 154Dy in proton-irradiated Ta, Pb, and W targets were re-evaluated, which are now in agreement with theoretical calculations.

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617.

In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [225Ac]Ac-PSMA-617. In vitro, [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their 177Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.8-fold and 1.4-fold increased for [225Ac]Ac-SibuDAB as compared to [177Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [225Ac]Ac-SibuDAB in the blood than previously seen for [177Lu]Lu-SibuDAB. Similar to [225Ac]Ac-PSMA-617, [225Ac]Ac-SibuDAB was well tolerated at 30 kBq per mouse. Differences in blood cell counts were observed between treated mice and untreated controls, but no major variations were observed between values obtained for [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617. [225Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [225Ac]Ac-PSMA-617. Only 5 kBq per mouse were sufficient to eradicate the tumors, whereas tumor regrowth was observed for mice treated with 5 kBq [225Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [225Ac]Ac-SibuDAB as compared to that of [225Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer.

Cross section measurement of terbium radioisotopes for an optimized 155Tb production with an 18 MeV medical PET cyclotron.

155Tb [t1/2 = 5.32 d, Eγ = 87 keV (32%); 105 keV (25%) (IAEA, 2021)] is a novel promising radionuclide for theranostic applications in nuclear medicine. Its physical properties make it suitable for single photon emission computed tomography (SPECT) imaging, while its chemistry allows it to be used as a diagnostic partner for therapeutic radiolanthanides or pseudo-radiolanthanides, such as 177Lu and 90Y. Moreover, 155Tb could be used as a precise diagnostic match for the ß--emitter 161Tb, opening doors for the true theranostics concept. The availability of 155Tb in quantity and quality suitable for medical applications is an open issue and its production with medical cyclotrons via the 155Gd(p,n)155Tb and 156Gd(p,2n)155Tb nuclear reactions represents a possible but challenging solution. For this purpose, an accurate knowledge of the production cross sections is mandatory. In this paper, we report on the measurement of the production cross sections of 155Tb and other terbium radionuclides formed by proton irradiation of natGd2O3, 155Gd2O3 and 156Gd2O3 enriched targets, performed at the Bern University Hospital cyclotron laboratory. On the basis of the obtained results, the production yield and purity were calculated to assess the optimal irradiation conditions. The results of several production tests are also presented.

Precise activity measurements of medical radionuclides using an ionization chamber: a case study with Terbium-161.

BACKGROUND: 161Tb draws an increasing interest in nuclear medicine for therapeutic applications. More than 99% of the emitted gamma and X-rays of 161Tb have an energy below 100 keV. Consequently, precise activity measurement of 161Tb becomes inaccurate with radionuclide dose calibrators when using inappropriate containers or calibration factors to account for the attenuation of this low energy radiation. To evaluate the ionization chamber response, the sample activity must be well known. This can be performed using standards traceable to the Système International de Référence, which is briefly described as well as the method to standardize the radionuclides. METHODS: In this study, the response of an ionization chamber using different container types and volumes was assessed using 161Tb. The containers were filled with a standardized activity solution of 161Tb and measured with a dedicated ionization chamber, providing an accurate response. The results were compared with standardized solutions of high-energy gamma-emitting radionuclides such as 137Cs, 60Co, 133Ba and 57Co. RESULTS: For the glass vial type with an irregular glass thickness, the 161Tb measurements gave a deviation of 4.5% between two vials of the same type. The other glass vial types have a much more regular thickness and no discrepancy was observed in the response of the ionization chamber for these type of vials. Measurements with a plastic Eppendorf tube showed stable response, with greater sensitivity than the glass vials. CONCLUSION: Ionization chamber measurements for low-energy gamma emitters (< 100 keV), show deviation depending on the container type used. Therefore, a careful selection of the container type must be done for activity assessment of 161Tb using radionuclide dose calibrators. In conclusion, it was highlighted that appropriate calibration factors must be used for each container geometry when measuring 161Tb and, more generally, for low-energy gamma emitters.