Underscoring the influence of inorganic chemistry on nuclear imaging with radiometals

Abstract

Over the past several decades, radionuclides have matured from largely esoteric and experimental technologies to indispensible components of medical diagnostics. Driving this transition, in part, have been mutually necessary advances in biomedical engineering, nuclear medicine, and cancer biology. Somewhat unsung has been the seminal role of inorganic chemistry in fostering the development of new radiotracers. In this regard, the purpose of this Forum Article is to more visibly highlight the significant contributions of inorganic chemistry to nuclear imaging by detailing the development of five metal-based imaging agents: (64)Cu-ATSM, (68)Ga-DOTATOC, (89)Zr-transferrin, (99m)Tc-sestamibi, and (99m)Tc-colloids. In a concluding section, several unmet needs both in and out of the laboratory will be discussed to stimulate conversation between inorganic chemists and the imaging community.

Figure 1

Illustration of the variety of metals with isotopes suitable for nuclear imaging. Elements with isotopes suitable for PET are color-coded blue, and elements with isotopes suitable for SPECT are color-coded red. The shading corresponds to half-life, with longer half-lives darker and shorter half-lives lighter. Elements with multiple shadings have multiple isotopes suitable for imaging.

Figure 2

(A) Structures of hypoxia-selective Cu-ATSM and nonselective Cu-PTSM. (B) Possible mechanistic scheme for the uptake and retention of Cu-ATSM in hypoxic cells.

Figure 3

Transaxial CT (top left), ¹⁸F-FDG PET (top right), ⁶⁰Cu-ATSM PET (bottom left), and ⁶⁴Cu-ATSM PET (bottom right) of two patients with cancer of the uterine cervix. Panel A displays the images from a patient who responded to therapy, whereas panel B displays the images of a nonresponder. This research was originally published in the Journal of Nuclear Medicine (see ref 130). Copyright 2008 Society of Nuclear Medicine and Molecular Imaging, Inc.

Figure 4

(A) Somatostatin; (B) octreotide; (C) ¹¹¹In-DTPA-labeled octreotide.

Figure 5

(A) Small-animal PET images using ⁶⁸Ga-DOTATOC showing tumor delineation in a mouse bearing subcutaneous xenografts that express different levels of SSTr2 (CT = C6-SSTr2, JT = Jurkat-SSTr2, and UT = U87-SSTr2; SSTr2 expression CT > UT > JT). This research was originally published in the Journal of Nuclear Medicine (see ref 131). Copyright 2011 Society of Nuclear Medicine and Molecular Imaging, Inc. (B) ⁶⁸Ga-DOTATOC PET images (left, anterior view; right, posterior view) of a patient with SSTr(+) abdominal lymph nodes (arrows). (C) SPECT images of ¹¹¹In-DTPA-octreotide in the same patient displaying reduced resolution. Adapted and reprinted with kind permission from ref . Copyright 2007 Springer Science + Business Media.

Figure 6

Macrocyclic ligands NOTA (A) and TRAP-Pr (B) and acyclic chelators H₂dedpa (C) and CP256 (D) have better Ga³⁺-chelating properties than DOTA based on thermodynamic stability and apotransferrin ligand-exchange tests.

Figure 7

(A) Structure of DFO. (B) Simple binding scheme of Zr⁴⁺ with DFO. (C) Calculated DFT structure of Zr⁴⁺ with DFO. Adapted with permission from ref . Copyright 2012 Elsevier Publishing Group, Inc.

Figure 8

Representative coronal slices of a coregistered PET/CT showing the distribution of ⁸⁹Zr-Tf in a genetically engineered mouse with prostate-specific overexpression of MYC. The animal was 12 months old, a time point at which invasive adenocarcinoma had developed. The images were acquired 16 h postinjection of ⁸⁹Zr-Tf. Ex vivo analysis confirmed uptake of the radiotracer in malignant tissue. Abbreviations: H = heart; L = liver; B = bladder; PCa = prostate cancer. This research was originally published in Nature Medicine (see ref 231). Copyright 2012 Nature Publishing Group, Inc.

Figure 9

(A) Structure of ^99mTc-sestamibi. (B) ^99mTc-sestamibi SPECT scintigraphy looking at myocardial perfusion. A 54-year-old man with acute anterior myocardial infarction initially presented with a perfusion defect of the anteroseptal and apical territories of the heart (left), but 4 months later, perfusion defect and ischemia were significantly reduced (right). Adapted and reprinted with kind permission from ref . Copyright 2010 Springer Science + Business Media.

Figure 10

^99mTc-sulfur-colloid SPECT lymphoscintigraphy. Anterior (A) and right-lateral (B) transmission images obtained 30 min after injection of ^99mTc-sulfur-colloid into the left breast show the injection site (solid arrow) and focal uptake (dashed arrow) in the sentinel node in the right axilla. This research was originally published in the Journal of Nuclear Medicine (see ref 263). Copyright 2006 Society of Nuclear Medicine and Molecular Imaging, Inc.