Radiochemistry for positron emission tomography

Abstract

Positron emission tomography (PET) constitutes a functional imaging technique that is harnessed to probe biological processes in vivo. PET imaging has been used to diagnose and monitor the progression of diseases, as well as to facilitate drug development efforts at both preclinical and clinical stages. The wide applications and rapid development of PET have ultimately led to an increasing demand for new methods in radiochemistry, with the aim to expand the scope of synthons amenable for radiolabeling. In this work, we provide an overview of commonly used chemical transformations for the syntheses of PET tracers in all aspects of radiochemistry, thereby highlighting recent breakthrough discoveries and contemporary challenges in the field. We discuss the use of biologicals for PET imaging and highlight general examples of successful probe discoveries for molecular imaging with PET - with a particular focus on translational and scalable radiochemistry concepts that have been entered to clinical use.

Fig. 1. Principle of positron emission tomography (PET) imaging.

1) Radionuclide generation. 2) Tracer synthesis. 3) Quality control (QC). 4) Intravenous tracer injection. 5) PET scan: positron decay, annihilation, and coincidence detection. 6) Image analysis and data quantification. Created with BioRender.com.

Fig. 2. Carbon-11 chemistry.

a ¹¹C-methylation with [¹¹C]CH₃I or [¹¹C]CH₃OTf (N-, O-, S-, C-¹¹C-methylation). b Synthesis of [¹¹C]carboxylic acids. c Synthesis of [¹¹C]aldehydes and [¹¹C]ketones.

Fig. 3. Carbon-11 Chemistry part 2.

a Synthesis of [¹¹C]carboxylic acid derivatives ([¹¹C]amides, [¹¹C]esters etc). b Synthesis of [¹¹C]carbamates, [¹¹C]dithiocarbamates, [¹¹C]ureas, and [¹¹C]thioureas. c Synthesis of [¹¹C]nitriles. d ¹¹C-Labeling with [¹¹C]CF₃ group.

Fig. 4. Fluorine-18 chemistry.

a Nucleophilic ¹⁸F-Fluorination. b ¹⁸F-labeling of non-activated arenes.

Fig. 5. Fluorine-18 chemistry part 2.

a Electrophilic ¹⁸F-fluorination. b Labeling with ¹⁸F-multifluoromethyl motifs. c ¹⁸F-labeling via B-, Si-, Al-, or S-¹⁸F bond formation.

Fig. 6. I-124/Br-76 chemistry.

a Nucleophilic ¹²⁴I-iodination. b Electrophilic ¹²⁴I-iodination. c Electrophilic ⁷⁶Br-bromination.

Fig. 7. Selected FDA-approved small molecule-based PET radiopharmaceuticals.

A number of small molecules labeled with F-18, C-11, and N-13 have been approved by FDA and used as PET radiopharmaceuticals.

Fig. 8. Radiometal chemistry for PET.

a Schematic diagram for radiometal-based PET radiopharmaceuticals (M*-C-L-TV). b Chelators in radiometal-based PET pharmaceuticals (acyclic chelators, cyclic chelators, and cross-bridged cyclic chelators). c Likers in metal-based radiopharmaceuticals (short sequences of amino acids, polyethylene glycols (PEG), and hydrocarbon chains). d Clinical examples of radiometal-based PET pharmaceuticals. Created with BioRender.com.

Fig. 9. Conventional vs. modern (Click-type) bioconjugation chemistry.

A While peptides and proteins were traditionally labeled via NH₂- and thiol-specific modification with N-hydroxysuccinimides (NHS), isothiocyanates, or maleimides, respectively, B modern (Click-type) bioconjugation strategies involve fast and high-yielding orthogonal radiochemistry with non-naturally occurring chemical functionalities. Created with BioRender.com.