Table 3.
Reporter genes and corresponding radionuclide imaging agents
| Class | Radiopharmaceutical probe | Sites of endogenous expression | Properties |
|---|---|---|---|
| Transporter | Sodium iodide symporter (NIS, SLC5A5) | ||
| PET: 124I−, [18F]BF4−, [18F]SO3F−, [18F]PF6−; SPECT: 99mTcO4−, 123I− | thyroid glands, stomach, small intestine, lacrimal glands, lactating mammary glands, choroid plexus, testicles | Na+ symport alongside various anions; several tracers clinically approved, most not requiring a cyclotron (99mTcO4−, xyzI−) or made by automated synthesis; tracers do not cross BBB | |
| Norepinephrine transporter (NET) | |||
| PET: [124I]MIBG, [18F]MIBG, [18F]PFBG, [11C]hydroxyephedrine; SPECT: [123I]MIBG | organs with central and peripheral sympathetic innervation (brain, heart) | NaCl-dependent monoamine transporter; tracers do not cross BBB | |
| Dopamine transporter (DAT) | |||
| PET: [11C]CFT, [11C]PE2I, [18F]FP-CIT; SPECT: [123I]-β-CIT, [123I]-FP-CIT, [123I]-ioflupane, 99mTRODAT | dopaminergic areas of the brain (striatum, substantia nigra, ventral tegmental area) | NaCl-dependent transport; tracers do cross BBB | |
| Pyruvate kinase M2 | |||
| PET: [18F]DASA-23 | central nervous system (CNS), lungs, liver, colon, thyroid, kidneys, bladder and several tumor types (breast, gastric, and colorectal) | suggested for CNS imaging; tracers do cross BBB | |
| Cell surface receptor | Somatostatin receptor type 2 (SSTR2) | ||
| PET: [68Ga]-DOTATOC, [68Ga]-DOTATATE; SPECT: [111In]-DOTA-BASS, [111In]-DTPA-octreotide; [99mTc]demotate 1, [99mTc]P829, [188Re]P829 | brain, adrenal glands, gastrointestinal tract, kidneys, spleen, tumors (i.e., pituitary, neuroendocrine, SCLC, pancreatic, paraganglioma, medullary thyroid carcinoma, pheochromocytomas) | G protein-coupled receptor; tracers responsible for cell signaling, change in proliferation, and might impair cell function; non-metal octreotide can cross the BBB; some radiotracers already in use in the clinics (i.e., 111In- and 68Ga-based) | |
| Dopamine receptor (D2R) and mutant (D2R80A) | |||
| PET: [18F]FESP, [11C]raclopride, [11C]N-methylspiperone | striatum and pituitary gland | G protein-coupled receptor; slow clearance observed for [18F]FESP; tracers do cross BBB | |
| Cell surface antigen | Human carcinoembryonic antigen (CEA)a | ||
| PET: [124I]-anti-CEA scFv-Fc H310A antibody fragment, [18F]FB-T84.66 diabody; SPECT: [99mTc]-anti-CEA Fab′, [111In]-ZCE-025, 111In-anti-CEA F023C5ia | not expressed in healthy adults, with the exception of colon lumen; overexpressed in pancreatic, gastric, colorectal and medullary thyroid cancers | [99mTc]-anti-CEA Fab′ is FDA approved; tracers do not cross BBB | |
| DOTA antibody reporter 1 (DAbR1, 2D12.5/G54C), C8.2.5 | |||
| PET: for DAbR1 [86Y]-AABD, [177Lu]-AABD | N/A | murine-derived scFv anti-DOTA IgG1 antibody fused to human CD4 TM domain; DOTA-complex tracer irreversibly binds to the cysteine residue (G54C) of the antibody; tracers do not cross BBB | |
| Cell surface protein | Glutamate carboxypeptidase 2 (PSMA, FOLH1) and variants (tPSMAN9Del, tPSMAW2G)a | ||
| PET: [18F]DCFPyL, [18F]DCFBC; SPECT: [125I]DCFPyL; anti-PSMA antibodies and ligands can be flexibly labeled, e.g., J591-IR800 | prostate, salivary glands, kidneys | anti-PSMA antibodies and ligands can be flexibly labeled, e.g., J591-IR800; risk of in vivo deiodination for radio-iodinated tracers, resulting in uptake in NIS-expressing organs; tracers do not cross BBB | |
| Artificial cell surface molecule | Anti-PEG Fab fragmenta | ||
| PET: 124I-PEG-SHPP | N/A | PEG is not toxic and is approved by the FDA; risk of in vivo deiodination for radio-iodinated tracers | |
| Human estrogen receptor α ligand binding domain (hERL) | |||
| PET: [18F]FES | uterus, ovaries, and mammary glands | does not report on cellular function; tracer is clinically used but does cross the BBB | |
| Enzyme | hmtk2 and mutants (hΔTK2, N93D/L109F) | ||
| PET: [124I]FIAU, [18F]FEAU, [18F]FMAU (hTK2-N93D/L109F) | all tissues (mitochondrial expression); hΔTK2 mutant expressed in the cell cytoplasm; high expression in gall bladder, intestine, and organs involved in clearance | cellular tracer trapping; tracers do not cross the BBB | |
| hdCK | |||
| PET: [124I]FIAU, [18F]FEAU | gall bladder, intestine, and organs involved in clearance | cellular tracer trapping; tracers do not cross the BBB | |
| HSV1-tk and mutants (HSV1-sr39tk and HSV1-A167Ytk) | |||
| PET: [124I]FIAU, [18F]FEAU, [18F]FHBG; other tracers are: [18F]FCAU, [18F]FBAU, [18F]FFEAU, [18F]FMAU, [18F]FHBT | N/A | non-mammalian kinase, potentially immunogenic; tracers do not cross the BBB, unless the latter is compromised; high activity in organs involved in clearance; kinase causes cellular tracer trapping and displays suicide gene properties | |
| β-galactosidase | |||
| PET: 2-(4-[123I]iodophenyl)ethyl-1-thio-β-d-galactopyranoside, 3- (2′-[18F]fluoroethoxy)-2- nitrophenyl-β-d- galactopyranoside, 3- [11C]methoxy-2-nitrophenyl-β-d- galactopyranoside, [18F]FPyGal; SPECT: 5-[125I]iodoindol-3-yl-β-d- galactopyranoside ([125I]IBDG) | N/A | glycoside hydrolase encoded by LacZ and isolated from E. coli; cellular toxicity may change with substrate; [125I]IBDG has a very fast clearance if systemically administered | |
FDA, US Food and Drug Administration; IgG1, immunoglobulin G1; N/A, not applicable; PSMA, prostate-specific membrane antigen; scFv, single-chain variable fragment; SCLC, small cell lung cancer; TM, transmembrane; tPSMA, truncated PSMA.
a
Compatibility with other imaging modalities provided that a suitable contrast forming moiety will be attached (CEA and PEG antibodies, respectively).