This review article explores the evolving landscape of Molecular Radiotherapy (MRT), emphasizing Peptide Receptor Radionuclide Therapy (PRRT) for neuroendocrine tumours (NETs). The primary focus is on the transition from β-emitting radiopharmaceuticals to α-emitting agents in PRRT, offering a critical analysis of the radiobiological basis, clinical applications, and ongoing developments in Targeted Alpha Therapy (TAT). Through an extensive literature review, the article delves into the mechanisms and effectiveness of PRRT in targeting somatostatin subtype 2 receptors, highlighting both its successes and limitations. The discussion extends to the emerging paradigm of TAT, underlining its higher potency and specificity with α-particle emissions, which promise enhanced therapeutic efficacy and reduced toxicity. The review critically evaluates preclinical and clinical data, emphasizing the need for standardised dosimetry and a deeper understanding of the dose-response relationship in TAT. The review concludes by underscoring the significant potential of TAT in treating SSTR2-overexpressing cancers, especially in patients refractory to β-PRRT, while also acknowledging the current challenges and the necessity for further research to optimize treatment protocols.

Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as catalysts. Targeted alpha emitters are in current development for several potential oncologic indications. Herein, we review the three most prevalently studied conjugated/chelated alpha emitters (225actinium, 212lead, and 211astatine) and focus on contemporary clinical trials in an effort to more fully appreciate the breadth of the current evaluation. Phase I trials targeting multiple diseases are now underway, and at least one phase III trial (in selected neuroendocrine cancers) is currently in the initial stages of recruitment. Combination trials are now also emerging as alpha emitters are integrated with other therapies in an effort to create solutions for those with advanced cancers. Despite the promise of targeted alpha therapies, many challenges remain. These challenges include the development of reliable supply chains, the need for a better understanding of the relationships between administered dose and absorbed dose in both tissue and tumor and how that predicts outcomes, and the incomplete understanding of potential long-term deleterious effects of the alpha emitters. Progress on multiple fronts is necessary to bring the potential of targeted alpha therapies into the clinic.

Objective. A systematic review of dosimetry in Targeted Alpha Therapy (TAT) has been performed, identifying the common issues.Approach. The systematic review was performed in accordance with the PRISMA guidelines, and the literature was searched using the Scopus and PubMed databases.Main results. From the systematic review, three key points should be considered when performing dosimetry in TAT. (1) Biodistribution/Biokinetics: the accuracy of the biodistribution data is a limit to accurate dosimetry in TAT. The biodistribution of alpha-emitting radionuclides throughout the body is difficult to image directly, with surrogate radionuclide imaging, blood/faecal sampling, and animal studies able to provide information. (2) Daughter radionuclides: the decay energy of the alpha-emissions is sufficient to break the bond to the targeting vector, resulting in a release of free daughter radionuclides in the body. Accounting for daughter radionuclide migration is essential. (3) Small-scale dosimetry and microdosimetry: due to the short path length and heterogeneous distribution of alpha-emitters at the target site, small-scale/microdosimetry are important to account for the non-uniform dose distribution in a target region, organ or cell and for assessing the biological effect of alpha-particle radiation.Significance. TAT is a form of cancer treatment capable of delivering a highly localised dose to the tumour environment while sparing the surrounding healthy tissue. Dosimetry is an important part of treatment planning and follow up. Being able to accurately predict the radiation dose to the target region and healthy organs could guide the optimal prescribed activity. Detailed dosimetry models accounting for the three points mentioned above will help give confidence in and guide the clinical application of alpha-emitting radionuclides in targeted cancer therapy.

Neuroendocrine neoplasms (NENs) are a very diverse group of tumors with a worldwide rise in incidence. Systemic therapy remains the mainstay treatment for unresectable and/or metastatic NENs. 177Lu-DOTATATE, a radiopharmaceutical which emits beta particles, has emerged as a promising therapy for metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, limited treatment options are available particularly after the failure of 177Lu-DOTATATE therapy. This review aims to identify and summarize the available evidence for, and potential adverse events of, targeted alpha-particle therapy (TAT) in the treatment of metastatic NENs, specifically GEP-NENs. The MEDLINE, EMBASE, SCOPUS, and Cochrane Library databases were searched. Two articles which met the inclusion criteria were identified and included in the review. Putative radiopharmaceuticals that can be considered for metastatic NEN treatment include 225Actinium (225Ac)-DOTATATE and 213Bismuth (213Bi)-DOTATOC. There was evidence of partial response using both radiopharmaceutical agents without significant hematological, renal, or hepatotoxicity. Future studies should consider longer term, randomized controlled trials investigating the role of TAT, in particular, 225Ac-DOTATATE, in the treatment of metastatic NENs.

This manuscript describes the history of 2 patients with prostate cancer (PCa) and the role of prostate-specific membrane antigen (PSMA) theranostics in their clinical management. In the first patient, PSMA-directed positron emission tomography (PET)/computed tomography (CT) imaging was used for primary staging of high-risk PCa before initial therapy. Then after biochemical relapse it was used to plan the scope of further treatment, in which it allowed among others to perform precise target volume delineation for salvage radiotherapy for pathologic lymph nodes. In the second patient with metastatic castration-resistant prostate cancer (mCRPC), PSMA-guided imaging played a key role in the qualification for PSMA-directed radioligand therapy (RLT) with lutetium-177. We also present a review of the current literature concerning PSMA theranostics in the 2 clinical settings, ie, primary staging of PCa and PSMA RLT of mCRPC. In the first part of the review, we report on the diagnostic efficacy of various PSMA imaging radiotracers labeled with gallium-68, fluorine-18, and technetium-99m. In the second part, we describe the limitations and future perspectives of PSMA therapeutic radiopharmaceuticals, including various beta(-) and alpha emitters.