Production of a broad palette of positron emitting radioisotopes using a low-energy cyclotron: Towards a new success story in cancer imaging?

Highlights

• The criteria for selection of PET radioisotopes is discussed.

• Positron emitting radioisotopes are categorized based on their stage of advancement.

• Production methodologies and the radiochemical separation procedures are discussed.

Abstract

Over the last several years, positron emission tomography (PET) has matured as an indispensable component of cancer diagnostics. Owing to the large variability observed among the cancer patients and the need to personalize individual patient's diagnosis and treatment, the need for new positron emitting radioisotopes has continued to grow. This mini review opens with a brief introduction to the criteria for radioisotope selection for PET imaging. Subsequently, positron emitting radioisotopes are categorized as: established, emerging and futuristic, based on the stages of their advancement. The production methodologies and the radiochemical separation procedures for obtaining the important radioisotopes in a form suitable for preparation of radiopharmaceuticals for PET imaging are briefly discussed.

Introduction

Cancer has become a global menace over the years and in today's world it is a major impediment to social and economic advances. Approximately 38 million people worldwide die of non-communicable diseases (NCDs) every year, out of which more than 9 million deaths are only due to cancer (Cancer Statistics, 2021; Lopez-Gomez et al., 2013; Global Cancer Observatory, 2020; Sung et al., 2021). According to the Global Cancer Observatory, it is estimated that there will be 15–17 million new cancer cases every year, of which 60% will be from the developing countries (Global Cancer Observatory, 2020; Sung et al., 2021). However, cancer related mortality can be significantly reduced provided it is detected at a very early stage. With current resources, one-third of newly diagnosed cancer patients could experience significantly increased survival, thanks to early-stage detection. In this endeavor, molecular imaging technology has emerged as one of the main pillars of comprehensive cancer care facilitating early diagnosis by non-invasive visualization and real time monitoring without tissue destruction (Bhanji et al., 2021; Chen et al., 2014; Jokar et al., 2021; Pysz et al., 2010; Wu and Shu, 2018).

Among the various molecular imaging modalities, positron emission tomography (PET) offers picomolar sensitivity and is a fully translational technique (Bhanji et al., 2021; Dagallier et al., 2021; Li and Conti, 2010; Slart et al., 2021; Zanoni et al., 2021). This approach requires specific molecular probes radiolabeled with positron-emitting radioisotopes having suitable radioactive decay parameters. The radioisotope incorporated in the molecular probe decays resulting in the emission of positrons which interact with nearby electrons after travelling a short distance (~ 1 mm) within the body. Each positron-electron annihilation process produces two γ-photons each of 511-keV in opposite directions, which are detected by the detectors surrounding the subject to precisely locate the source of the decay event (Fig. 1A). Subsequently, the ‘coincidence events’ data can be processed by computers to reconstruct the spatial distribution of the radiolabeled molecular probes and the PET images thus generated can reflect the concentration and in vivo distribution of the radiotracer administered (Fig. 1B). This technology provides highly sensitive and quantitative information and is playing an increasingly important role in earlier disease detection and improved therapeutic decision making.

Over the last three decades, PET has matured from a largely obscure and experimental technology to an indispensable constituent of routine nuclear medicine practices. Driving this transition, in part, have been mutually necessary advances in instrumentation and biomedical engineering, radiopharmaceutical chemistry and cancer biology. Somewhat unsung has been the seminal role of radioisotope production technology in fostering the availability of new PET radiotracers for improved cancer imaging and this review is an attempt to rectify this oversight. The positron emitting radioisotopes used for PET, being neutron deficient, are generally produced in cyclotron. Presently, more and more countries around the world are investing heavily on installation and commissioning of new cyclotron facilities, which are mostly low energy cyclotrons exclusively for production of medically important radioisotopes. In this review, we will first discuss the criteria for radioisotope selection for PET imaging. Then, we categorize the positron emitting radioisotopes produced in low energy cyclotrons as: established, emerging and futuristic. Thereafter, we discuss briefly regarding the production methodologies and the radiochemical separation procedures for obtaining the radioisotopes in a form suitable for preparation of radiopharmaceuticals for PET imaging.