Perspectives and trends in radiopharmaceutical Chemistry

Radiopharmaceutical Chemistry has dramatically developed for over five decades together with the wide availability of an increasing number of artificially produced radioisotopes. Target and radionuclide chemistry, new labelling methods for radiohalogens and carbon-11 and radiometal chemistry are providing the tools that are required to meet the challenge of radiopharmaceutical development. The preparation and handling of radionuclides and radiopharmaceuticals has become a specialized function, and application of radioactive diagnostic and therapeutic agents constitutes one of the great advances in non-invasive medicine.
Diagnostic radiopharmaceuticals make the human body biochemically transparent with respect to individual molecular reactions. Conventional imaging with radiotracers based on the readily available generator nuclide technetium-99m or iodine-123 as well as positron emission tomography (PET), mainly with [¹⁸F]fluorodeoxyglucose, have done much to localize and recognize lesions and to predict the efficacy of treatment. The focus of radiopharmaceutical research is on the development of new tracers that bind preferentially to specific sites of action which diagnostics or therapy can be based upon. This involves the design and development of tracers for apoptosis, hypoxia, angiogenesis, detection of unstable plaques, gene therapy monitoring, imaging cardiac innervation, antibody-based reactions and a vast array of ligand-receptor interactions. Cell membrane and intracellular receptors have become a major domain of radiopharmaceutical research, involving neurotransmitters, hormones, growth factors, and cytokines. For example, new development of analogues, chelators and radionuclides leads to progress in peptide receptor imaging. While numerous radiolabelling peptides are being studied, the majority are those that target somatostatin receptors present on various tumours. The future application of radiolabelled peptides in tumour scintigraphy may be aimed at their in vivo use as prognostic predictors.

Targeted radiotherapy with peptides labelled with radionuclides emitting alpha or beta particles, or Auger or conversion electrons may become a new cancer treatment modality. This orientation has provided an impetus to research in the production and chemistry of new therapeutic radionuclides (e.g. ¹¹¹In, ^103mRd, ⁶⁷Cu, ¹⁷⁷Lu, ⁹⁰Y, ¹⁸⁸Re, ²¹¹At, ²¹¹Bi, ²¹³Bi), as well as new bifunctional chelators. The advantages of targeted "cell surgery" with radiotherapeutics appears obvious. Therefore, continuing improvements are to be expected. The advent of selective targeting of radiolabelled monoclonal antibodies against tumour-associated antigens is a major breakthrough not only for cancer detection and monitoring, but also for therapy. So far, radioimmunotherapy has been more successful in the radiosensitive haematological malignancies. E.g. lymphomas and leukaemia's as compared with solid tumours. Progress in radiometal coordination chemistry and the ability to generate new constructs, such as bivalent antibodies or fusion proteins will hopefully open opportunities for new radiotherapeutics.

Radioactive compounds have been applied in creative ways to study drug action directly in laboratory animals and in humans. Because both drug pharmacokinetics and drug pharmacodynamics can be measured, radiotracer development both for labelled drugs and for labelled tracers is a key area in this field. The short half-lives of the radionuclides set limits to the period of the studies. For direct measurements of drug pharmacokinetics the drug usually must be labelled with carbon-11 to avoid changing the characteristics of the parent molecule. Fluorine-18 also is used if the drug has a fluorine atom. PET also made it possible to assess the effects of drugs on e.g. glucose metabolism, blood flow or neurotransmission using well-est...