PET imaging with ⁸⁹Zr: from radiochemistry to the clinic

Abstract

The advent of antibody-based cancer therapeutics has led to the concomitant rise in the development of companion diagnostics for these therapies, particularly nuclear imaging agents. A number of radioisotopes have been employed for antibody-based PET and SPECT imaging, notably ⁶⁴Cu, ¹²⁴I, ¹¹¹In, and (99m)Tc; in recent years, however, the field has increasingly focused on ⁸⁹Zr, a radiometal with near ideal physical and chemical properties for immunoPET imaging. In the review at hand, we seek to provide a comprehensive portrait of the current state of ⁸⁹Zr radiochemical and imaging research, including work into the production and purification of the isotope, the synthesis of new chelators, the development of new bioconjugation strategies, the creation of novel ⁸⁹Zr-based agents for preclinical imaging studies, and the translation of ⁸⁹Zr-labeled radiopharmaceuticals to the clinic. Particular attention will also be dedicated to emerging trends in the field, ⁸⁹Zr-based imaging applications using vectors other than antibodies, the comparative advantages and limitations of ⁸⁹Zr-based imaging compared to that with other isotopes, and areas that would benefit from more extensive investigation. At bottom, it is hoped that this review will provide both the experienced investigator and new scientist with a full and critical overview of this exciting and fast-developing field.

Figure 1

(A) A simplified decay scheme of ⁸⁹Zr; (B) Some salient decay characteristics of ⁸⁹Zr; (C) Photograph of the custom-made water-cooled solid-target assembly for the TR19/9 cyclotron used at Memorial Sloan-Kettering Cancer; (D) A static 10 minute PET image recorded by using a Derenzo phantom, with corresponding hole diameters in mm. (C) and (D) are modified and reprinted from Holland, et al. Nucl Med Bio 2009; 36:729-39.

Figure 2

The ligand structure, coordination scheme, and experimental structure of some commonly-employed chelators for Zr⁴⁺ and their complexes with the metal.

Figure 3

Schematic of some common DFO conjugation strategies.

Figure 4

(A) Biodistribution of radioactivity at 6 days post-injection following i.v. administration of various chemical form of ⁸⁹Zr in female NIH Swiss mice (n ≥ 3; note the axis break). Reprinted with permission from Abou, et al. Nucl Med Bio 2011;38:675-81. (B) PET images showing maximum intensity projection of ⁸⁹Zr-oxalate at 24 h after intravenous administration and dynamic PET images of ⁸⁹Zr-DFO at 1 and 4 min after injection. Adapted with permission from Holland, et al. J Nucl Med 2010; 51: 1293-300.

Figure 5

Representative transversal and coronal small animal PET images of ⁸⁹Zr-bevacizumab obtained before treatment of A2780 (A) and CP70 (B) xenografts (left) and after NVP-AUY922 treatment (right). Images were obtained at 144 h after injection of 89Zr-bevacizumab. Tumor is indicated by arrow. Reprinted with permission from Nagengast, et al. J Nucl Med 2010; 51: 761-767.

Figure 6

⁸⁹Zr-5A10 detects pharmacologic inhibition of AR in vivo Left: representative transverse and coronal PET slices of intact male mice bearing LNCaP-AR xenografts on the right flank and imaged with ⁸⁹Zr-5A10 24 hours post-injection after manipulation with a subcutaneous testosterone pellet or a daily oral gavage of vehicle or MDV3100 for 7 days. Arrows indicate the position of the tumor (T) and the murine liver (L). Right: region-of-interest analysis of the tumors from the PET study shows statistically significant changes in tumor-associated ⁸⁹Zr-5A10. *P , 0.01 compared with vehicle. **P , 0.05 compared with vehicle. Error bars represent the standard deviation from mean. Reprinted with permission from Ulmert, et al. Cancer Discovery 2012; ASAP.

Figure 7

ImmunoPET images with ⁸⁹Zr-cmAb U36 of head and neck cancer patient with a tumor in the left tonsil (large arrow) and lymph node metastases (small arrows) at the left (level II and III) and right (level II) side of the neck. Images were obtained 72 hours post-injection. A: sagittal image; B: axial image; and C: coronal image. Reprinted with permission from Borjesson, et al. Clinical Cancer Research 2006; 12: 2133-40.

Figure 8

Examples of fusion images from ⁸⁹Zr-Trasutuzmab PET and MRI scans. (a) In a vertebral metastasis seen on MRI but unapproachable for biopsy, HER2 status was revealed by ⁸⁹Zr-trastuzumab uptake on PET imaging. (b) Example of HER2-positive brain lesion undetected by conventional scans, revealed by ⁸⁹Zr-trastuzumab PET imaging, and subsequently confirmed by MRI. Arrows indicate lesions. Reprinted with permission from Dijkers, et al. J Nucl Med 2009; 50: 974-81.

Figure 9

¹⁸F-FDG (13.2 mCi), ¹⁸F-NaF (10.2 mCi), and ⁸⁹Zr-DFO-J591 (4.8 mCi) sagittal PET images of a 56 year-old male with castrate-resistant prostate cancer. Images courtesy of Drs. J. Carrasquillo, M. Morris, and S.M. Larson, MSKCC.