Alpha vs. Beta Emitters in Radioligand Therapy: How to Choose the Right Isotope

Introduction

According to the European Organisation for Research and Treatment of Cancer (EORTC), Radioligand Therapy (RLT) is an oncology treatment that couples a therapeutic radioactive isotope with a cancer-specific cell targeting molecule, known as the ligand. When the ligand binds to the cancer cell, radioactivity is released to destroy it. Due to some milestone RLT approvals in recent years, research and development into this novel therapeutic is expanding, with pharmaceutical sponsors increasingly investing in radiopharmaceutical discovery, translational research, and clinical programs in an effort to expand potential targets, isotopes, and tumor indications. While RLT is a promising area of research, development can be time-consuming, costly, and ineffective if it is not designed and planned effectively. One particular area of focus is radiopharmaceutical isotope selection, which directly influences therapeutic efficacy, safety, and clinical trial design. This article will consider the choice between Alpha vs Beta emitters within radioligand therapy development, considering their distinct properties, therapeutic use cases, and study design implications, to guide sponsors in making effective and practical trial decisions.

An introduction to radiopharmaceutical isotope selection

There are currently over 400 radiopharmaceutical trials registered on clinicaltrials.gov looking into the development and use of an estimated 10-15 different isotopes, for both diagnostic and therapeutic use. A radiopharmaceutical isotope, or radioisotope, is the unstable form of an element that emits radiation as it transforms into a more stable state. Radiation can be easily traced and measured, making it instrumental for clinical imaging, but when coupled with a cancer-specific ligand, it can selectively destroy cancerous cells while sparing healthy surrounding tissue.

While there are over 3,000 different isotopes, the radiation emitted from each can be grouped most commonly as alpha, beta, and gamma particles, each having distinct physical properties and biological effects. The characteristics of each isotope determine whether or not it is suitable for use in clinical imaging and therapeutics, making radiopharmaceutical isotope selection central to RLT decision-making and clinical trial design. Gamma radiation is rarely used therapeutically, rather diagnostically, owing to its high tissue penetration and limited ability to selectively destroy cancer cells, so radiopharmaceutical isotope selection is generally focused on alpha emitters vs beta emitters.

Alpha emitters vs Beta emitters

Alpha and Beta emitters have distinct properties and clinical implications, meaning the choice of isotope must be carefully considered within the research context, considering tumor type, therapeutic or diagnostic goals, and balancing efficacy, safety, and potential toxicity.

Take Actinium-225 vs Lutetium-177, for example. Lutetium-177, or Lu-177, is a medium-energy beta emitter, and marked one of the first RLT approvals in 2018 for its use in certain Gastroenteropancreatic neuroendocrine tumors, which has since expanded into PSMA-positive metastatic castration-resistant prostate cancer. Actinium-225, or (²²⁵Ac), is a targeted alpha therapy, harnessing an alpha-emitting radionuclide, and while it is not yet approved, studies have shown remarkable promise, particularly within the context of advanced prostate cancer. Each isotope has been chosen with specific therapeutic intent in mind: Lu-177 for treating small cluster tumor cells with moderate tissue penetration and manageable logistics, ²²⁵Ac for highly potent, localised cell damage in micro metastatic or minimal residual disease settings.

While beta emitters currently represent the majority of radionuclides employed within RLT, one global comparison of targeted alpha vs targeted beta therapy for cancer concluded that alpha therapy could be superior to targeted beta therapy in terms of efficacy within the tolerance dose; however, due to certain practical considerations, its clinical use remains restricted.

See the table below for a comparison of the properties and uses of Alpha emitters vs Beta emitters:

Aligning trial design using a strategic partner

Producing high-quality radionuclides requires expertise and specialized facilities, and RLT drug development require trained experts, well-established quality assurance processes, and experience driving regulatory compliance in radiochemistry. Radiopharmaceutical isotope selection directly influences study design and ultimately, its success, impacting patient selection, dosing, scheduling, and safety monitoring, all of which must be carefully aligned with the physical properties of the isotope and the therapeutic intent of the research.

Offering radioligand discovery support, Perceptive leverages in-house expertise and a well-established global infrastructure to guide isotope selection and radiochemistry optimization, ensuring the success of your radioligand therapy trial.

• 900+ agents radiolabeled
• Extensive experience with US and UK/EU GMP regulatory requirements
• 80+ IND submissions supported for novel radiotracers
• Significant supply chain capabilities, supporting 300 global production centers
• External manufacturing offering covering the US, EU, APAC, and Oceania, including site identification, qualification, set up, validation, and oversight

For radiopharmaceutical isotope selection guidance, contact a solutions specialist today, or click to learn more about Perceptive Discovery: https://www.perceptive.com/radiochemistry/

Resources

1. EORTC. Radioligand Therapy. https://www.eortc.org/scientific-strategy/radioligand-therapy-rlt/ 
2. IAEA. Radioisotopes. https://www.iaea.org/topics/nuclear-science/isotopes/radioisotopes 
3. Critical Reviews in Oncology/Hematology. Global comparison of targeted alpha vs targeted beta therapy for cancer: In vitro, in vivo, and clinical trials. https://www.sciencedirect.com/science/article/pii/S1040842817303608