Nuclear Imaging Probes: from Bench to Bedside

The availability of specific imaging probes is the nuclear fuel for molecular imaging by positron emission tomography and single-photon emission computed tomography. These two radiotracer-based imaging modalities represent the prototype methods for noninvasive depiction and quantification of biochemical processes, allowing a functional characterization of tumor biology. Avariety of powerful radiolabeled probes!tracers!are already established in the routine clinical management of human disease and others are currently subject to clinical assessment. Emerging from investigations of the genomic and proteomic signatures of cancer cells, an increasing number of promising targets are being identified, including receptors, enzymes, transporters, and antigens. Corresponding probes for these newly identified targets need to be developed and transferred into the clinical setting. Starting with a brief summary of the characteristics and prerequisites for a ‘‘good tracer,’’ an overview of tracer concepts, target selection, and development strategies is given. The influence of the imaging concepts on tracer development is also discussed. The term ‘‘molecular imaging,’’ currently defined as ‘‘in vivo imaging of biological or biochemical processes,’’ originally describes the visualization of a target molecule in vivo by virtue of its interaction with a probe at the molecular level. In recent years, the field of molecular imaging has broadened and includes several different modalities [e.g., nuclear imaging, magnetic resonance imaging, magnetic resonance spectroscopy, computed tomography (CT), ultrasound, bioluminescence, and fluorescence imaging; ref. 1]. Among these modalities, nuclear molecular imaging with positron emission tomography (PET) and single-photon emission CT represent the prototype for noninvasive quantitative tracing of biochemical processes in vivo. A radiolabeled compound is applied to follow a pathway (transport rate, binding capacity, metabolic rate, etc.) and to detect the utilization of an endogenous analogue (ion, substrate, hormone, etc.) or the expression pattern and density of its corresponding biochemical counterpart (transporter, receptor, enzyme, etc.). To avoid any disturbance of the biochemical or kinetic equilibrium of the process being studied, no-carrier-added tracer preparations without macroscopic or pharmacologic amounts of the respective nonlabeled analogue are applied. A radiopharmaceutical administered at the tracer (no carrier added) level will optimally reach concentrations at the target site in vivo in the picomolar to femtomolar range. According to the law of mass action, binding of a compound in such a low concentration to a target structure (e.g., a receptor) requires a binding affinity constant (Ka) in the high picomolar to low nanomolar range. Assuming that the molecular target relevant to the disease of interest is differentially overexpressed and accessible for the probe, the signal ‘‘detected by PET’’ provides a tomographic (three dimensional), quantitative data set of the target distribution and density. In addition, using sophisticated tracer kinetic modeling, kinetic variables, such as equilibrium or flux constants, can be calculated. The nuclear tracer technique in combination with PET imaging has advanced the functional evaluation of cancer in vivo . 2-[F]fluoro-2-deoxy-D-glucose ([F]FDG; Fig. 1) constitutes a large part of the success story of PET and is extensively used for diagnosis, staging, and therapy control of cancer. But other radiopharmaceuticals, addressing proliferation, hypoxia, angiogenesis, apoptosis, receptor expression, metastasis, or gene transfection, have also been established in part in the clinic (2) and continue to be developed in preclinical and clinical studies (Fig. 2). Key Steps in the Development of Nuclear Probes The development of a probe for nuclear molecular imaging requires the following key questions to be addressed. (a) Is the target specific for the disease of interest and can it be relevantly addressed by a radiolabeled probe? To provide a functional characterization of a disease process, the target density, and thus the tracer uptake, has to be representative of the extent and progression of the disease. (b) Is there existing a molecule (e.g., an enzyme, receptor ligand, peptide, or antibody) with relevant target affinity and suitability to serve as a lead for the development as a tracer? (c) The physiochemical behavior of the tracer in vivo should correspond with the half-life of the isotope (e.g., half-life: C = 20 min, F = 110 min, and Ga = 68 min). Is it possible to modify and optimize the lead Author’s Affiliation: Department of Nuclear Medicine, Technische Universita« t Mu« nchen, Munich, Germany Received 2/1/07; revised 4/12/07; accepted 4/13/07. Grant support: BavarianMinistry of Science, Research and Arts (BayGene). Requests for reprints: Hans-Ju« rgenWester, Department of Nuclear Medicine, Technische Universita« t Mu« nchen, Ismaninger Strasse 22, 81675 Munich, Germany. Phone: 49-89-41-40-45-86/49-89-41-40-29-73; E-mail: [email protected]. F2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-0264 www.aacrjournals.org Clin Cancer Res 2007;13(12) June15, 2007 3470 CCR FOCUS Research. on January 29, 2018. © 2007 American Association for Cancer clincancerres.aacrjournals.org Downloaded from molecule about radiolabeling strategy, in vivo stability, clearance route and kinetics, specificity of binding, and background radioactivity levels? (d) Does the tracer accumulation in vivo correlate with the biochemical process? This most relevant validation and final preclinical milestone has to be evaluated in suitable animal models, with human tumor xenografts potentially serving as the first relevant proof of the hypothesized target/tracer concept. (e) Can the imaging concept developed and validated in animals be translated to man? The validation step in man requires independent assays on tissue samples obtained from biopsies and surgical specimens. Consequently, the transfer of a new nuclear imaging probe from bench to bedside is a complex multidisciplinary process. Some of the issues about the aforementioned questions and concepts for PET tracers are discussed in more detail in this article based in examples of clinical relevancy.