Figure 2.

Mechanisms of radionuclide imaging (SPECT/PET) reporter genes and examples from oncolytic virotherapy and gene therapy studies

(A) NIS expressed on the cell surface concentrates ∗I (∗I indicates it can be ¹²³I, ¹²⁴I, ¹²⁵I, or ¹³¹I) radiotracer into the cell. Decay of ∗I radiotracers directly releases (¹²³I/¹²⁵I/¹³¹I) or leads to the release (¹²⁴I) of gamma (γ) photons for SPECT or PET imaging. Imaging panel: 3D reconstruction of PET/CT imaging of mice infected with AAV-9-CAG-human NIS or minke whale NIS in the absence or presence of the NIS inhibitor perchlorate (ClO₄). (B) HSV1-tk: Radiolabeled substrates like [∗I]-FIAU can pass in and out of the cell until they are phosphorylated by HSV1-tk to yield [∗I]-FIAU-PO₄, which becomes trapped intracellularly. Upon radioactive decay, ∗I releases γ photons for capture via SPECT/PET. Imaging panel: 9-[4-[^18F] fluoro-3-(hydroxymethyl) butyl] guanine (¹⁸F-FHBG) uptake in the liver and injection site (arrow) of a self-complementary recombinant AAV-3 vector expressing HSV1-tk and kallistatin. (A) depicts coronal slices of an animal’s PET imaging (left) and image of maximum intensity projection (right). (B) depicts transverse, coronal, and sagittal images of the PET/CT. (C) NET: NET transports radiolabeled norepinephrine analogs like [∗I]-meta-iodobenzylguanidine (∗I-MIBG) into the cell, where γ photons are released upon radioactive decay. Imaging panel: HepG2 tumors in mice infected with an adenovirus expressing NET. ¹³¹I γ-camera images 30 min (a), 1 h (b), 4 h (c), and 24 h (d) after radiotracer administration. Radiotracer collects in the bladder non-specifically for excretion. (D) SSTR2: Radiolabeled peptides (such as ⁶⁸Ga-DOTATE) bind to the SSTR2 receptor and γ photons are released upon radioactive decay. SSTR2 is the only nuclear transgene depicted which cannot amplify its signal due to the 1:1 receptor:peptide binding stoichiometry. Imaging panel: Infection of HT29 tumors with oncolytic vaccinia virus expressing SSTR2 (VV-SSR2) and SPECT imaging with ¹¹¹In-octreotide 4 days after virus treatment. Figure made with BioRender (https://biorender.com/) and Photoshop CC 2019. Protein shapes are artistic interpretations. Permissions for imaging panels: (A) From Concilio et al.⁴² and reproduced under CC Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/). (B) From Liu et al.⁴³ and reproduced under CC Attribution License (https://creativecommons.org/licenses/by/4.0/). (C) From Jia et al.⁴⁴ and reproduced with licensed permission. (D) From Wang et al.⁴⁵ and reproduced with permission from the journal; this research was originally published in JNM.