A review of imaging agent development

Abstract

This educational review highlights the processes, opportunities, and challenges encountered in the discovery and development of imaging agents, mainly positron emission tomography and single-photon emission computed tomography tracers. While the development of imaging agents parallels the drug development process, unique criteria are needed to identify opportunities for new agents. Imaging agent development has the flexibility to pursue functional or nonfunctional targets as long as they play a role in the specific disease or mechanism of interest and meet imageability requirements. However, their innovation is tempered by relatively small markets for diagnostic imaging agents, intellectual property challenges, radiolabeling constraints, and adequate target concentrations for imaging. At the same time, preclinical imaging is becoming a key translational tool for proof of mechanism and concept studies. Pharmaceutical and imaging industries face a common bottleneck in the form of the limited number of trials one company can possibly perform. However, microdosing and theranostics are evidence that partnerships between pharmaceutical and imaging companies can accelerate clinical translation of tracers and therapeutic interventions. This manuscript will comment on these aspects to provide an educational review of the discovery and development processes for imaging agents.

Fig. 1

Discovery and development of therapeutics and diagnostics. a Therapeutic process modified from Fig. 4 of the FDA’s Critical Path Initiative; $3.4 billion annual revenue is representative of a typical top ten selling drug. b The best selling diagnostic imaging agent has an annual revenue of $400 million. Cost and timeline numbers taken from Nunn (10)

Fig. 2

The iterative discovery process allows for the early in vivo assessment of novel imaging compounds and targeting mechanisms

Fig. 3

Three classes of tracers (modified from Dilworth and Parrott (55)). a Class 1 tracers are those where the radionuclide is the imaging agent itself. Class 2 tracers have pendent radiolabels. Class 3 incorporates the radionuclide within the targeting molecule. b (1) [Tc-99m]TRODAT-1, (2) Experimental [Tc-99m]estradiol. c (3) [Ga-68]DOTATOC, (4) [C-11]DOPA, (5) 3-N-(2[F-18]Fluoroethyl)spiperone

Fig. 4

Stages in preclinical and clinical therapeutic development paired with measurable end points using molecular imaging (modified from Workman et al. (113))

Fig. 5

a Baseline [F-18]FDG PET images of a patient with squamous cell carcinoma of the pyriform fossa with left nodal mass. b [F-18]FMISO PET at baseline with nonhypoxic primary tumor and hypoxic node. c [F-18]FDG PET 12 weeks after chemotherapy, complete response in nonhypoxic primary tumor and poor response in hypoxic node. Hypoxic node identified for tirapazamine treatment (images from Rischin et al. (115))