Chemistry and Radiochemistry

Radionuclides and radionuclide production

Note: The terms ‘Isotope’ or ‘Radioisotope’ are commonly but incorrectly used to denote the radioactive elements used in the labelling of radiopharmaceuticals. The readers are encouraged to adopt the correct terminology ‘Radionuclide(s)‘ instead. These and other commonly used terms and radiochemistry concepts are defined and exemplified in[31].

The standard way of denoting radionuclides is as follows: ¹³N, ¹¹C, ¹⁸F, ⁶⁴Cu, ⁸⁹Zr or alternatively zirconium-89 etc. (not N-13, 89-Zr etc.)

Radionuclides are commonly produced by a number of methods:

1. Cyclotron accelerates high energy particles (typically protons, deuterons, or, with high energy cyclotrons, also alpha particles), which are aimed at stable materials in a so-called target (e.g. nitrogen gas, oxygen-18 enriched water). The latter undergo nuclear fragmentation upon being hit by the particle beam to give rise to the new radionuclides (e.g.¹⁸F, ¹¹C, ¹³N, ¹⁵O, ⁶⁴Cu, ⁸⁹Zr, ¹²³I) [32] [33]
2. Nuclear reactor produced radionuclides (e.g. ³²P, ⁹⁹Mo, ¹³¹I, ¹⁷⁷Lu) can be divided into two groups: radionuclides formed via fission reaction (⁹⁹Mo, ¹³¹I) and radionuclides produced via neutron activation ³²P, ¹⁷⁷Lu: [34], ⁹⁹Mo, ¹³¹I: [35]  ¹⁷⁷Lu:[36]. 
3. Radionuclide generator contains a long-lived parent radionuclide (⁶⁸Ge, ⁹⁹Mo, ⁶²Zn, ⁸²Sr), which decays to a short-lived daughter radionuclide (e.g. ⁶⁸Ga, ^99mTc, ⁶²Cu, ⁸²Rb). The parent radionuclides for these generators are either cyclotron or nuclear reactor produced [37,38].

Choice of Radionuclide

The choice of radionuclide for a particular application may depend on a number of factors:

• Radionuclide for diagnostic imaging applications
  • Imaging modality to be used (e.g. gamma emitter for SPECT, positron emitter for PET)
  • The biological half-life of the in vivo process under study should match the radioactive half-life of the radionuclide used. For example, blood flow is a rapid biological process (in the order of minutes) and can be easily followed using radiopharmaceuticals having short half-lives (e.g. [¹⁵O]water, [¹³N]ammonia (radioactive half-lives of 2 and 10 min, respectively). Antibody targeting typically has a longer biological half-life of days or weeks. In this case a ⁸⁹Zr- or ¹²⁴I- (radioactive half-lives 3.27 and 4.18 days) labelled protein might be an appropriate choice of radionuclide.
  • Small molecules and peptides – the biological half-lives of these are often in the range of hours. In this case, labelling with intermediate half-life radionuclides (e.g. ¹¹C, ¹⁸F, ⁶⁴Cu, ^99mTc etc., radioactive half-lives 20 and 110 min, 12.7 and 6 h, respectively) is usually required.
     
• Radionuclide for therapeutic applications
  • type of decay (α or β)
  • Emitted radiation energy
  • Radioactive half-life
  • [¹³¹I]Iodine or [²²³Ra]RaCl2 are used without further chemical processing. Others e.g. ⁹⁰Y[39] and ¹⁷⁷Lu are used to label molecules such as antibodies and peptides.
  • Linear Energy Transfer (LET) (the decay chain of a radionuclide should be considered, how many alphas/betas generated before decaying to a stable nuclide)

Radionuclide processing

The radionuclides obtained from a generator, cyclotron or reactor (typically termed ‘primary labelling precursor’) are obtained in simple ionic or molecular forms. As such, they are not necessarily useful as imaging agents themselves (exceptions are [¹⁸F]fluoride and [^99mTc]pertechnetate). Synthetic chemistry techniques are used to incorporate these primary precursors into a molecule of interest directly or via the generation of intermediate labelled building blocks (often termed secondary radiolabelling precursors (e.g. [¹¹C]methyl iodide, 2-[¹⁸F]fluoroethyl tosylate). Each of the steps in the synthetic process (from primary precursor through to final product) should be carefully optimized to reduce production times and maximize yields and quality of the radiopharmaceutical products. Such optimization may include choice of the reaction solvent, reaction temperatures, improvements in technical handing, purification, etc.

Synthesis modules: automation / purification / formulation and sterilization

In order to reduce radiation exposure to staff in the processing of radionuclides from primary precursor through to final purified product, these activities are often performed behind lead shields (lead bricks, hot-cells) often using automated devices. There are numerous manufacturers of these ‘synthesis modules’ for a wide variety of radiopharmaceuticals. The final product may need purification (e.g. HPLC, solid phase extraction) prior to formulation and sterilization. The latter is most frequently performed by passage of the formulated product over a 0.22 micrometre micromembrane filter into a sterile vial and/or autoclaving (reference). Kits containing reagents and consumables are commercially available for a number of radiotracers.