Since prostate cancer is the most commonly diagnosed malignancy in men, the theranostic approach has become very attractive since the discovery of urea-based PSMA inhibitors. Different molecules have been synthesized starting from the Glu-urea-Lys scaffold as the pharmacophore and then optimizing the linker and the chelate to improve functional characteristics. This article aimed to highlight the quality aspects, which could have an impact on clinical practice, describing the development of an Investigational Medicinal Product Dossier (IMPD) for clinical trials with [¹⁷⁷Lu]Lu-PSMA-I&T in prostate cancer and other solid tumors expressing PSMA. The results highlighted some important quality issues of the final preparation: radiolabeling of PSMA-I&T with lutetium-177 needs a considerably longer time compared with the radiolabeling of the well-known [¹⁷⁷Lu]Lu-PSMA-617. When the final product was formulated in saline, the stability of [¹⁷⁷Lu]Lu-PSMA-I&T was reduced by radiolysis, showing a decrease in radiochemical purity (<95% in 24 h). Different formulations of the final product with increasing concentrations of ascorbic acid have been tested to counteract radiolysis and extend stability. A solution of 20 mg/mL of ascorbic acid in saline prevents radiolysis and ensures stability over 30 h.

The radionuclide⁸⁹Zr (T_1/2=78.4ߙh) is particularly attractive for in vivo assessment of biochemical proesses characterized by biological half times in the order of several hours. In the present study we assessed the feasibility of⁸⁹Zr productionviathe⁸⁹Y(p,n)⁸⁹Zr reaction. Irradiation tests were performed using a 16.5ߙMeV GE-PETtrace cyclotron. High purity (>99.9%) yttrium metallic foils (0.15ߙmm) were irradiated in a solid target station developed in our Institution. The literature cross section data of all the nuclear reactions possible in the energy range of interest were carefully studied to optimize the irradiation parameters. The irradiated target was dissolved in 1ߙN HCl and the activity of the sample was measured in a CRC-15 PET dose calibrator, setting different values for the calibration factor. The sample activity was then measured usin g a calibrated HPGe gamma ray detector. A comparison of the activity measurements allowed the evaluation of the calibration factor for the Capintec CRC-15 PET; for a 3ߙml syringe geometry, it was found 739±60. Saturation yields of⁸⁹Zr were found to be 1150±110ߙMBq/μA for a single 0.15ߙmm thick disc irradiation (E_p=12.6→11.2ߙMeV) and 2400±220ߙMBq/μA for irradiation of two discs of total thickness 0.3ߙmm (E_p=12.6→9.5MeV). Total produced activities in the range of 200–400ߙMBq (according to target thickness) were repeatedly and safely obtained by 60ߙmin bombardments at 20ߙμA. Analysis of gamma ray spectra of all the samples showed a very high radionuclidic purity (>99.9995%).

This review comprehensively assesses the clinical applications and future potential of alpha-emitting radionuclides available for targeted alpha-particle therapy (TAT) in cancer treatment. The approval of radium-223 therapy in 2013 marked a significant advancement in alpha-emitting therapeutic radiopharmaceuticals, which are primarily used in treatment of prostate cancer. The EU SECURE project was introduced as a major initiative to enhance the sustainability and safety of medical alpha-emitting radionuclides production in Europe. This literature review was conducted by a multidisciplinary team on selected radionuclides, including actinium-225, bismuth-213, astatine-211, lead-212, terbium-149, radium-223 and thorium-227. These were selected based on their clinical significance, as identified in the EU PRISMAP project and subsequent literature searches. The review process involved searching major databases using specific keywords related to alpha-emitter therapy and was limited to articles in English. For each selected radionuclide, the physical characteristics, the radiochemistry, and the pre-clinical and clinical studies are explored. Actinium-225 is the most widely studied alpha emitter, with several preclinical and clinical studies on prostate cancer and neuroendocrine tumours. Other types of tumours (such as glioblastoma) still require preclinical and clinical development. Bismuth-213 bound to antibodies, peptides and nanobodies has shown optimal results in preclinical and clinical studies, with increased median survival and no significant toxicity. Astatine-211 differs from most other α-emitters relevant to TAT, since it yields one α-particle per decay. This offers certain translational advantages, including the simplification of radiation dosimetry calculations and quality control (QC). Lead-212 has the advantage of being an in situ generator with likely widespread availability. Although clinical data are limited, the findings are promising at this stage. The unconventional production of Terbium-149 is the primary reason it has not yet progressed to clinical trials. Overcoming this production obstacle would allow more detailed preclinical investigations. Optimal results with Thorium-227-labelled agents have been observed in preclinical studies, including delays in cellular growth, multiple double-strand breaks and complete regression. Intermediate phase I trial results have also been reported, demonstrating safety and tolerability, as well as an objective response rate of 25%.: The results highlight the advantages of alpha particles in targeting cancer cells with minimal radiation to normal tissue, emphasising the need for high specificity and stability in delivery mechanisms, as well as suggesting that the full clinical potential of alpha particle therapy remains unexplored. Theranostic approach and dosimetric evaluations still represent relevant challenges.

Background/Objectives The document comprehensively reviews the clinical applications and future potential of alpha-emitting radionuclides available for targeted alpha-particle therapy (TAT) in cancer treatment. The approval of radium-223 (Ra-223) therapy in 2013 marked a significant advancement in alpha-emitting therapeutic radiopharmaceuticals, which are primarily used in treatment of prostate cancer. The EU SECURE project was introduced as a major initiative to enhance the sustainability and safety of medical alpha-emitting radionuclides production in Europe. Methods: This literature review was conducted by a multidisciplinary team on selected radionuclides, including actinium-225, bismuth-213, astatine-211, lead-212, terbium-149, radium-22323 and thorium-227. These were selected based on their clinical significance, as identified in the EU PRISMAP project and subsequent literature searches. The review process involved searching major databases using specific keywords related to alpha-emitter therapy and was limited to articles in English. For each selected radionuclide, the physical characteristics, the radiochemistry, and the pre-clinical and clinical studies are explored. Results of the review show current and potential clinical applications of new alpha-emitting radionuclides, sharing insights from the SECURE consortium’s experiences and providing recommendations for future clinical trials to establish the therapeutic efficacy of these radionuclides. Conclusion: For each selected radionuclide, conclusion are reported in individual chapters. The results highlight the advantages of alpha particles in targeting cancer cells with minimal radiation to normal tissue, emphasising the need for high specificity and stability in delivery mechanisms, but also suggest that the full clinical potential of alpha particle therapy remains unexplored. Theranostic approach and dosimetric evaluations still represent relevant challenges.

Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold standard for PET imaging of prostate cancer. [⁶⁸Ga]Ga-PSMA-11 has been the forerunner but a [¹⁸F]F-PSMA ligand has been developed because of the intrinsic advantages of Fluorine-18. Fluorine-18 labelled compounds are usually prepared in centers with an on-site cyclotron. Since our center has not an on-site cyclotron, we decided to verify the feasibility of producing the experimental ¹⁸F^-labelled radiopharmaceutical [¹⁸F]F-PSMA-1007 with [¹⁸F]F^- from different external suppliers. A quality agreement has been signed with two different suppliers, and a well-established and correctly implemented quality assurance protocol has been followed. The [¹⁸F]F^- was produced with cyclotrons, on Nb target, but with different beam energy and current. Extensive validation of the [¹⁸F]F-PSMA-1007 synthesis process has been performed. The aim of this paper was the description of all the quality documentation which allowed the submission and approval of the Investigational Medicinal Product Dossier (IMPD) to the Competent Authority, addressing the quality problems due to different external suppliers. The result indicates that no significant differences have been found between the [¹⁸F]F^- from the two suppliers in terms of radionuclidic and radiochemical purity and [¹⁸F]F^- impacted neither the radiochemical yield of the labelling reaction nor the quality control parameters of the IMP [¹⁸F]F-PSMA-1007. These results prove how a correct quality assurance system can overcome some Regulatory Authorities issue that may represent an obstacle to the clinical use of F-18-labelled radiopharmaceuticals without an on-site cyclotron.