TABLE 2.
Promising host-compatible reporter genes and their corresponding imaging tracers.
| Reporter | Reporter in vivo detection | ||||
| Class | Name | Properties | Imaging modality and contrast agent | Contrast agent properties | References |
| Transporter | Sodium iodide symporter (NIS) | Symports Na+ alongside various anions. Endogenous expression in thyroid, stomach, lacrimal, salivary and lactating mammary glands, small intestine, choroid plexus and testicles. | PET: 124I–, [18F]BF4–, [18F]SO3F–, [18F]PF6–. SPECT: 99mTcO4–, 123I–. | Tracers do not cross BBB. | (Dai et al., 1996; Jauregui-Osoro et al., 2010; Khoshnevisan et al., 2016, 2017; Jiang et al., 2018) |
| Norepinephrine transporter (NET) | NaCl-dependent monoamine transporter. Endogenously expressed in organs with sympathetic innervation (heart, brain), | PET: [124I]MIBG**; [11C]hydroxyephedrine. SPECT: [123I]MIBG**. | Tracers do not cross BBB. | (Moroz et al., 2007) | |
| Dopamine transporter (DAT) | NaCl-dependent. | PET: [11C]CFT, [11C]PE2I, [18F]FP-CIT. SPECT: 123I-β-CIT**, 123I-FP-CIT**, 123I-Ioflupane**, 99mTRODAT. | Few data in public domain. Tracers cross BBB. | (UCL Business PLC, 2017) | |
| Enzyme | Pyruvate kinase M2 | Expression during development, also in cancers. | PET: [18F]DASA-23. | Background in organs of excretion route. Suggested for cell tracking within brain. Tracer crosses BBB. | (Haywood et al., 2019) |
| Thymidine kinase (hmtk2/hΔTK2) | Human kinase causing cellular tracer trapping. | PET: [124I]FIAU**, [18F]FEAU, [18F]FMAU (for hTK2-N93D/L109F). | Tracers do not cross the BBB; Endogenous signals in gall bladder, intestine and organs involved in clearance. | (Ponomarev et al., 2007) | |
| Deoxycytidine kinase (hdCK) | Human kinase causing cellular tracer trapping. | PET: [124I]FIAU**, [18F]FEAU. | Tracers do not cross the BBB; Endogenous signals in gall bladder, intestine and organs involved in clearance. | (Likar et al., 2010; Lee et al., 2017) | |
| Cell surface receptor | Somatostatin receptor type 2 (SSTr2) | G-protein-coupled receptor. Endogenous expression in brain, adrenal glands, kidneys, spleen, stomach and many tumors (i.e., SCLC, pituitary, endocrine, pancreatic, paraganglioma, medullary thyroid carcinoma, pheochromocytoma); | PET: 68Ga-DOTATOC, 68Ga-DOTATATE. SPECT: 111In-DOTA-BASS. (best tracers selected here). | Tracers may cause cell signaling, change proliferation and might inhibit impair cell function. Non-metal octreotide radiotracers can cross blood brain barrier (BBB). | (Rogers et al., 1999, 2000; Zinn et al., 2000a, b; Chaudhuri et al., 2001) |
| Dopamine receptor (D2R) | G-protein-coupled receptor. High endogenous expression in pituitary gland and striatum. | PET: [18F]FESP, [11C]Raclopride, [11C]N-methylspiperone. | Slow clearance of [18F]FESP; Tracers cross BBB. | (Satyamurthy et al., 1990; MacLaren et al., 1999; Liang et al., 2001; Hwang et al., 2007) | |
| Transferrin receptor (TfR) | Fast recycling receptor. | MRI: Transferrin-conjugated SPIO. | Transferrin-conjugated SPIOs are internalized by cells. | (Weissleder et al., 2000) | |
| Cell surface protein | Glutamate carboxy-peptidase 2 (PSMA) and variant tPSMAN9del | tPSMAN9del has higher plasma membrane concentration. High expression in prostate. | PET: [18F]DCFPyL, [18F]DCFBC. SPECT: [125I]DCFPyL**.anti-PSMA antibodies and ligands can be flexibly labeled*, e.g. J951-IR800. | Background signal in kidneys. Tracers do not cross BBB. | (Castanares et al., 2014; Minn et al., 2019) |
| Cell surface antigen | Human carcino-embryonic antigen (hCEA) | Overexpressed in pancreatic, gastric, colorectal and medullary thyroid cancers. | PET: 124I-anti-CEA scFv-Fc H310A**, [18F]FB-T84.66 diabody SPECT: 99mTc-anti-CEA Fab’ (approved), 111In-ZCE-025, 111In-anti-CEA F023C5i. | Tracers do not cross BBB. | (Griffin et al., 1991; Hammarstrom, 1999; Hong et al., 2008; Kenanova et al., 2009) |
| Artificial cell surface molecule | DOTA antibody reporter 1 (DAbR1) | ScFv of anti-DOTA antibody 2D12.5/G54C fused to human CD4 TM domain. | PET:86Y-AABD. | Tracer is a DOTA complex that binds irreversibly to a cysteine residue in the 2D12.5/G54C antibody. Tracer does not cross BBB. | (Wei et al., 2008) |
| Estrogen receptor α ligand binding domain | No reported physiological function. | PET: [18F]FES. | Tracer is clinically used estrogen receptor imaging agent. | (Qin et al., 2013) | |
| Anti-PEG Fab fragment* | Some tracers cross BBB; PEG is non-toxic and approved by FDA. | PET: 124I-PEG-SHPP*,**. MRI: SPIO-PEG. Fluorescence: e.g. NIR797-PEG. | Iodine tracers bear risk of deiodination. Some tracers cross BBB. | (Chuang et al., 2010) | |
| Carrier protein | Ferritin | MRI: iron. | Iron is not equally distributed across the brain and therefore may cause local susceptibility shifts that are above the MRI detection limit. | (Cohen et al., 2005; Genove et al., 2005) | |
Promise was evaluated based on (i) host-compatibility of the reporter and (ii) availability of contrast agents. *Any other modality can be used provided a suitable contrast forming moiety will be attached to PEG and the CEA antibodies, respectively. **Radioiodinated tracers can become de-iodinated in vivo resulting in free iodide that is subsequently taken up into NIS expressing organs.