Purpose: PET-imaging with the prostate-specific membrane antigen-targeted radioligand ⁶⁸Ga-PSMA-11 is regarded as a significant step forward in the diagnosis of prostate cancer (PCa). More recently, a PSMA-ligand was developed which can be labeled with ⁶⁸Ga, ¹¹¹In, ¹⁷⁷Lu, and ⁹⁰Y. This ligand, named PSMA-617, therefore enables both, diagnosis and therapy of PCa. The aim of this evaluation was to clinically investigate the distribution of ⁶⁸Ga-PSMA-617 in normal tissues and in PCa lesions as well as to evaluate the radiation exposure by the radioligand in PET-imaging. Methods: Nineteen patients, most of them with recurrent PCa, were referred to ⁶⁸Ga-PSMA-617-PET/CT. Quantitative assessment of tracer uptake of several organs and of 53 representative tumor lesions was performed in 15 patients at 1h and 3h post injection (p.i.). In four additional patients, the same procedure was conducted at 5min, 1h, 2h, 3h, 4h and 5h p.i. Based on the data of these four patients (mean injected dose of 231 MBq) the radiation exposure of a ⁶⁸Ga-PSMA-617-PET/CT was identified. Results: Intense tracer uptake was observed in kidneys and salivary glands. In 14 of 19 patients (73.7%) at least one tumor suspicious lesion was detected at 3h p.i. Of 53 representative tumor lesions selected at 3h p.i., 47 lesions were visible at 1h p.i. Mean tumor-to-background ratio for SUV_max was 20.4 ± 17.3 (2.3 – 84.0) at 1h p.i. and 38.2 ± 38.6 (3.6 – 154.3) at 3h p.i. Average radiation exposure (effective dose) was approximately 0.021 mSv/MBq. Conclusion: Within healthy organs, kidneys and salivary glands showed the highest ⁶⁸Ga-PSMA-617 uptake. The radiation exposure is relatively low. ⁶⁸Ga-PSMA-617 shows PCa-lesions with very high contrast. Images conducted between 2-3h p.i. seem to be the best option with regard to radiotracer uptake and tumor contrast. Later images can help to clarify unclear lesions.

In the United States, [⁶⁸Ga]Ga-DOTA-TOC has been approved by the Food and Drug Administration (FDA) in 2019 as the first ⁶⁸Ga-radiopharmaceutical for imaging of somatostatin receptor (SSTR) positive gastroenteropancreatic neuroendocrine tumors while employing positron emission tomography (PET). In Europe (Austria, Germany, France), [⁶⁸Ga]Ga-DOTA-TOC was already approved back in 2016. This radiopharmaceutical combines the radionuclide ⁶⁸Ga with the somatostatin analogue DOTA-TOC for specific imaging of tumor cells expressing SSTRs. Such a targeting approach can also be used for therapy planning in the case of both localized as well as disseminated disease and potentially for the evaluation of treatment response.

The use of radionuclides for targeted endoradiotherapy is a rapidly growing field in oncology. In particular, the focus on the biological effects of different radiation qualities is an important factor in understanding and implementing new therapies. Together with the combined approach of imaging and therapy, therapeutic nuclear medicine has recently made great progress. A particular area of research is the use of alpha-emitting radionuclides, which have unique physical properties associated with outstanding advantages, e.g., for single tumor cell targeting. Here, recent results and open questions regarding the production of alpha-emitting isotopes as well as their chemical combination with carrier molecules and clinical experience from compassionate use reports and clinical trials are discussed.

In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the landscape dramatically altered. Currently, men face a one-in-nine lifetime risk of PCa, accentuated by improved diagnostic methods and an ageing population. With more than three million men in the United States alone grappling with this disease, the overall risk of succumbing to stands at one in 39. The intricate clinical and biological diversity of PCa poses serious challenges in terms of imaging, ongoing monitoring, and disease management. In the field of theranostics, diagnostic and therapeutic approaches that harmoniously merge targeted imaging with treatments are integrated. A pivotal player in this arena is radiotheranostics, employing radionuclides for both imaging and therapy, with prostate-specific membrane antigen (PSMA) at the forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved PSMA-targeted radiodiagnostic agents, such as [¹⁸F]DCFPyL (PYLARIFY^®, Lantheus Holdings), [¹⁸F]rhPSMA-7.3 (POSLUMA^®, Blue Earth Diagnostics) and [⁶⁸Ga]Ga-PSMA-11 (Locametz^®, Novartis/ ILLUCCIX^®, Telix Pharmaceuticals), as well as PSMA-targeted radiotherapeutic agents, such as [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^®, Novartis). Concurrently, ligand-drug and immune therapies designed to target PSMA are being advanced through rigorous preclinical research and clinical trials. This review delves into the annals of PSMA-targeted radiotheranostics, exploring its historical evolution as a signature molecule in PCa management. We scrutinise its clinical ramifications, acknowledge its limitations, and peer into the avenues that need further exploration. In the crucible of scientific inquiry, we aim to illuminate the path toward a future where the enigma of PCa is deciphered and where its menace is met with precise and effective countermeasures. In the following sections, we discuss the intriguing terrain of PCa radiotheranostics through the lens of PSMA, with the fervent hope of advancing our understanding and enhancing clinical practice.

Atomic in vivo nanogenerators such as actinium-225, thorium-227, and radium-223 are of increasing interest and importance in the treatment of patients with metastatic cancer diseases. This is due to their peculiar physical, chemical, and biological characteristics, leading to astonishing responses in otherwise resistant patients. Nevertheless, there are still a few obstacles and hurdles to be overcome that hamper the broader utilization in the clinical setting. Next to the limited supply and relatively high costs, the in vivo complex stability and the fate of the recoiling daughter radionuclides are substantial problems that need to be solved. In radiobiology, the mechanisms underlying treatment efficiency, possible resistance mechanisms, and late side effect occurrence are still far from being understood and need to be unraveled. In this review, the current knowledge on the scientific and clinical background of targeted alpha therapies is summarized. Furthermore, open issues and novel approaches with a focus on the future perspective are discussed. Once these are unraveled, targeted alpha therapies with atomic in vivo nanogenerators can be tailored to suit the needs of each patient when applying careful risk stratification and combination therapies. They have the potential to become one of the major treatment pillars in modern cancer management.

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two ⁵⁵Co-labeled albumin-binding folate derivatives-[⁵⁵Co]Co-cm10 and [⁵⁵Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both ⁵⁵Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [⁶⁴Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors.