PurposeThe prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate 161Tb (T1/2 = 6.89 days; Eβ-uperscript>av = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to 177Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.Methods161Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177Lu-PSMA-617. The effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice.Results161Tb-PSMA-617 and 177Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to 161Tb-PSMA-617 as compared to the effect obtained with the same activities of 177Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 indicated the anticipated superiority of 161Tb over 177Lu.Conclusion161Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161Tb-PSMA-617 for the treatment of mCRPC.Electronic supplementary materialThe online version of this article (10.1007/s00259-019-04345-0) contains supplementary material, which is available to authorized users.

Currently, different radiometals are in use for imaging and therapy in nuclear medicine: Ga andIn are examples of nuclides for positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively, while Lu andAc are used for β- and α-radionuclide therapy. The application of diagnostic and therapeutic radionuclides of the same element (radioisotopes) would utilize chemically-identical radiopharmaceuticals for imaging and subsequent treatment, thereby enabling the radiotheranostic concept. There are two elements which are of particular interest in this regard: Scandium and Terbium. Scandium presents three radioisotopes for theranostic application. Sc (T = 3.9 h) and Sc (T = 4.0 h) can both be used for PET, while Sc (T = 3.35 d) is the therapeutic match-also suitable for SPECT. Currently, Sc is most advanced in terms of production, as well as with pre-clinical investigations, and has already been employed in proof-of-concept studies in patients. Even though the production ofSc may be more challenging, it would be advantageous due to the absence of high-energetic γ-ray emission. The development of Sc is still in its infancy, however, its therapeutic potential has been demonstrated preclinically. Terbium is unique in that it represents four medically-interesting radioisotopes.Tb (T = 5.32 d) and Tb (T = 17.5 h) can be used for SPECT and PET, respectively. Both radioisotopes were produced and tested preclinically. Tb has been the first Tb isotope that was tested (asTb-DOTATOC) in a patient. Both radionuclides may be of interest for dosimetry purposes prior to the application of radiolanthanide therapy. The decay properties of Tb (T = 6.89 d) are similar to Lu, but the coemission of Auger electrons make it attractive for a combined β/Auger electron therapy, which was shown to be effective in preclinical experiments. Tb (T = 4.1 h) has been proposed for targeted α-therapy with the possibility of PET imaging. In terms of production, Tb andTb are most promising to be made available at the large quantities suitable for future clinical translation. This review article is dedicated to the production routes, the methods of separating the radioisotopes from the target material, preclinical investigations and clinical proof-of-concept studies of Sc and Tb radionuclides. The availability, challenges of production and first (pre)clinical application, as well as the potential of these novel radionuclides for future application in nuclear medicine, are discussed.

BackgroundRadiotheragnostics makes use of the same molecular targeting vectors, labeled either with a diagnostic or therapeutic radionuclide, ideally of the same chemical element. The matched pair of scandium radionuclides, 44Sc and 47Sc, satisfies the desired physical aspects for PET imaging and radionuclide therapy, respectively. While the production and application of 44Sc was extensively studied, 47Sc is still in its infancy. The aim of the present study was, therefore, to investigate and compare two different methods of 47Sc production, based on the neutron irradiation of enriched 46Ca and 47Ti targets, respectively.Methods 47Sc was produced by thermal neutron irradiation of enriched 46Ca targets via the 46Ca(n,γ)47Ca → 47Sc nuclear reaction and by fast neutron irradiation of 47Ti targets via the 47Ti(n,p)47Sc nuclear reaction, respectively. The product was compared with regard to yield and radionuclidic purity. The chemical separation of 47Sc was optimized in order to obtain a product of sufficient quality determined by labeling experiments using DOTANOC. Finally, preclinical SPECT/CT experiments were performed in tumor-bearing mice and compared with the PET image of the 44Sc labeled counterpart.ResultsUp to 2 GBq 47Sc was produced by thermal neutron irradiation of enriched 46Ca targets. The optimized chemical isolation of 47Sc from the target material allowed formulation of up to 1.5 GBq 47Sc with high radionuclidic purity (>99.99%) in a small volume (~700 μL) useful for labeling purposes. Three consecutive separations were possible by isolating the in-grown 47Sc from the 46/47Ca-containing fraction. 47Sc produced by fast neutron irradiated 47Ti targets resulted in a reduced radionuclidic purity (99.95–88.5%). The chemical purity of the separated 47Sc was determined by radiolabeling experiments using DOTANOC achievable at specific activities of 10 MBq/nmol. In vivo the 47Sc-DOTANOC performed equal to 44Sc-DOTANOC as determined by nuclear imaging.ConclusionThe production of 47Sc via the 46Ca(n,γ)47Ca nuclear reaction demonstrated significant advantages over the 47Ti production route, as it provided higher quantities of a radionuclidically pure product. The subsequent decay of 47Ca enabled the repeated separation of the 47Sc daughter nuclide from the 47Ca parent nuclide. Based on the results obtained from this work, 47Sc shows potential to be produced in suitable quality for clinical application.Electronic supplementary materialThe online version of this article (doi:10.1186/s41181-017-0024-x) contains supplementary material, which is available to authorized users.

BackgroundRecently, 44Sc (T1/2 = 3.97 h, Eβ+ av = 632 keV, I = 94.3 %) has emerged as an attractive radiometal candidate for PET imaging using DOTA-functionalized biomolecules. The aim of this study was to investigate the potential of using NODAGA for the coordination of 44Sc. Two pairs of DOTA/NODAGA-derivatized peptides were investigated in vitro and in vivo and the results obtained with 44Sc compared with its 68Ga-labeled counterparts.DOTA-RGD and NODAGA-RGD, as well as DOTA-NOC and NODAGA-NOC, were labeled with 44Sc and 68Ga, respectively. The radiopeptides were investigated with regard to their stability in buffer solution and under metal challenge conditions using Fe3+ and Cu2+. Time-dependent biodistribution studies and PET/CT imaging were performed in U87MG and AR42J tumor-bearing mice.ResultsBoth RGD- and NOC-based peptides with a DOTA chelator were readily labeled with 44Sc and 68Ga, respectively, and remained stable over at least 4 half-lives of the corresponding radionuclide. In contrast, the labeling of NODAGA-functionalized peptides with 44Sc was more challenging and the resulting radiopeptides were clearly less stable than the DOTA-derivatized matches. 44Sc-NODAGA peptides were clearly more susceptible to metal challenge than 44Sc-DOTA peptides under the same conditions. Instability of 68Ga-labeled peptides was only observed if they were coordinated with a DOTA in the presence of excess Cu2+. Biodistribution data of the 44Sc-labeled peptides were largely comparable with the data obtained with the 68Ga-labeled counterparts. It was only in the liver tissue that the uptake of 68Ga-labeled DOTA compounds was markedly higher than for the 44Sc-labeled version and this was also visible on PET/CT images. The 44Sc-labeled NODAGA-peptides showed a similar tissue distribution to those of the DOTA peptides without any obvious signs of in vivo instability.ConclusionsAlthough DOTA revealed to be the preferred chelator for stable coordination of 44Sc, the data presented in this work indicate the possibility of using NODAGA in combination with 44Sc. In view of a clinical study, thorough investigations will be necessary regarding the labeling conditions and storage solutions in order to guarantee sufficient stability of 44Sc-labeled NODAGA compounds.Electronic supplementary materialThe online version of this article (doi:10.1186/s41181-016-0013-5) contains supplementary material, which is available to authorized users.

BackgroundThe favorable decay properties of 43Sc and 44Sc for PET make them promising candidates for future applications in nuclear medicine. An advantage 43Sc (T1/2 = 3.89 h, Eβ+ av = 476 keV [88%]) exhibits over 44Sc, however, is the absence of co-emitted high energy γ-rays. While the production and application of 44Sc has been comprehensively discussed, research concerning 43Sc is still in its infancy. This study aimed at developing two different production routes for 43Sc, based on proton irradiation of enriched 46Ti and 43Ca target material.Results 43Sc was produced via the 46Ti(p,α)43Sc and 43Ca(p,n)43Sc nuclear reactions, yielding activities of up to 225 MBq and 480 MBq, respectively. 43Sc was chemically separated from enriched metallic 46Ti (97.0%) and 43CaCO3 (57.9%) targets, using extraction chromatography. In both cases, ~90% of the final activity was eluted in a small volume of 700 μL, thereby, making it suitable for direct radiolabeling. The prepared products were of high radionuclidic purity, i.e. 98.2% 43Sc were achieved from the irradiation of 46Ti, whereas the product isolated from irradiated 43Ca consisted of 66.2% 43Sc and 33.3% 44Sc. A PET phantom study performed with 43Sc, via both nuclear reactions, revealed slightly improved resolution over 44Sc. In order to assess the chemical purity of the separated 43Sc, radiolabeling experiments were performed with DOTANOC, attaining specific activities of 5–8 MBq/nmol, respectively, with a radiochemical yield of >96%.ConclusionsIt was determined that higher 43Sc activities were accessible via the 43Ca production route, with a comparatively less complex target preparation and separation procedure. The product isolated from irradiated 46Ti, however, revealed purer 43Sc with minor radionuclidic impurities. Based on the results obtained herein, the 43Ca route features some advantages (such as higher yields and direct usage of the purchased target material) over the 46Ti path when aiming at 43Sc production on a routine basis.Electronic supplementary materialThe online version of this article (10.1186/s41181-017-0033-9) contains supplementary material, which is available to authorized users.