The next generation of positron emission tomography radiopharmaceuticals in oncology

Abstract

Although (18)F-fluorodeoxyglucose ((18)F-FDG) is still the most widely used positron emission tomography (PET) radiotracer, there are a few well-known limitations to its use. The last decade has seen the development of new PET probes for in vivo visualization of specific molecular targets, along with important technical advances in the production of positron-emitting radionuclides and their related labeling methods. As such, a broad range of new PET tracers are in preclinical development or have recently entered clinical trials. The topics covered in this review include labeling methods, biological targets, and the most recent preclinical or clinical data of some of the next generation of PET radiopharmaceuticals. This review, which is by no means exhaustive, has been separated into sections related to the PET radionuclide used for radiolabeling: fluorine-18, for the labeling of agents such as FACBC, FDHT, choline, and Galacto-RGD; carbon-11, for the labeling of choline; gallium-68, for the labeling of peptides such as DOTATOC and bombesin analogs; and the long-lived radionuclides iodine-124 and zirconium-89 for the labeling of monoclonal antibodies cG250, and J591 and trastuzumab, respectively.

Figure 1

Structures of ¹⁸F-choline and ¹⁸F-Galacto-RGD.

Figure 2

Synthesis of ¹⁸F-FDHT from the intermediate 16α-triflate.

Figure 3

Synthesis of ¹⁸F-FACBC from the hydantoin intermediate (major isomer).

Figure 4

For a representative axial slice, a CT image (A), an FACBC PET image (B), and a registered image (C) are shown; this figure demonstrates how the FACBC PET scan information was registered with the planning CT scan. (Adapted with permission from Jani AB, et al. Case study of anti-1-amino-3 ¹⁸F-fluorocyclobutane-1-carboxylic acid (anti-¹⁸F-FACBC) to guide prostate cancer radiotherapy target design. Clin Nucl Med 34:279–284, 2009.)

Figure 5

(A) Example of patient with resected paraganglioma and recurrent mass in retroperitoneum. Both tracers, ¹⁸F-FDG and ⁶⁸Ga-DOTATOC, showed clearly enhanced uptake in retroperitoneal mass seen on CT scan. (B) Both tracers demonstrated a metastatic lesion in lower lobe of left lung. The small pulmonary lesion (CT and zoom of the outlined red area) was better delineated on ⁶⁸Ga-DOTATOC study than on ¹⁸F-FDG study. (C) Another small lesion in upper left anterior mediastinum (CT overview and zoom of left anterior mediastinum) was clearly delineated on ⁶⁸Ga-DOTATOC study but not on ¹⁸F-FDG study. (With kind permission from Springer Science+Business Media: Koukouraki S, et al. Comparison of the pharmacokinetics of ⁶⁸Ga-DOTATOC and ¹⁸F-FDG in patients with metastatic neuroendocrine tumours scheduled for ⁹⁰Y-DOTATOC therapy. Eur J Nucl Med Mol Imaging 33:1115–1122, 2006.)

Figure 6

Schematic representation of ⁸⁹Zr-N-SucDFO-mAb conjugate. (Color version of figure is available online.)

Figure 7

Temporal immuno-PET images of ⁸⁹Zr-DFO-J591 (10.9–11.3 MBq [295–305 μCi], 60–62 μg of mAb, in 200 μL of sterile saline) recorded in LNCaP tumor-bearing (PSMA-positive, left shoulder) (A) and PC3 tumor-bearing (PSMA-negative, right shoulder) (B) mice between 3 and 144 hours after injection. Transverse and coronal planar images intersect center of tumors, and mean T/M ratios derived from volume-of-interest analysis of immuno-PET images are given. Upper thresholds of immuno-PET have been adjusted for visual clarity, as indicated by scale bars. (Reprinted by permission of the Society of Nuclear Medicine from: Holland JP, et al. ⁸⁹Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. J Nucl Med 51:1293–1300, 2010, Figure 4.)

Figure 8

Examples of ⁸⁹Zr-trastuzumab uptake 5 days after injection. (A) Patient with liver and bone metastases; (B and C) 2 patients with multiple bone metastases. Several lesions have been specifically indicated by arrows. (Reprinted by permission from Macmillan Publishers Ltd: Dijkers EC., et al. Biodistribution of ⁸⁹Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther 87:586–592, 2010.)