Table 1.

Promising Host-Compatible Reporter Genes and Their Corresponding Imaging Tracers

Reporter				Imaging Agent
Class	Name	Properties	aaa	Modality	Properties	Refs.
Transporter	sodium iodide symporter (NIS, SLC5A5)	symports Na+ alongside various anions; endogenous expression in thyroid, stomach, lacrimal, salivary, and lactating mammary glands, small intestine, choroid plexus, and testicles	618	PET: 124I−, [18F]BF4−, [18F]SO3F−, [18F]PF6−; SPECT: 99mTcO4−, 123I−	tracers do not cross the blood-brain barrier (BBB); several tracers are clinically approved, most require no cyclotron (99mTcO4−/xyI−) or are made by automated synthesis33	34, 35, 36,37,38
	norepinephrine transporter (NET, SLC6A2)	NaCl-dependent monoamine transporter; endogenously expressed in organs with sympathetic innervation (heart, brain)	617	PET: [124I]MIBG,b [11C]hydroxyephedrine; SPECT: [123I]MIBGb	tracers do not cross the BBB	39
	dopamine transporter (DAT, SLC6A3)	NaCl-dependent	620	PET: [11C]CFT, [11C]PE2I, [18F]FP-CIT; SPECT: 123I-β-CIT,b123I-FP-CIT,b123I-ioflupane,b99mTRODAT	few data in the public domain; tracers cross the BBB.	40
Enzyme	pyruvate kinase M2	expression during development, also in cancers	531	PET: [18F]DASA-23	background in organs of excretion route; suggested for cell tracking within brain; tracer crosses the BBB	41
	thymidine kinase (hmtk2/hΔTK2)	human kinase causing cellular tracer trapping	265	PET: [124I]FIAU,b [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	42
	deoxycytidine kinase (hdCK)	human kinase causing cellular tracer trapping	260	PET: [124I]FIAU,b [18F]FEAU	tracers do not cross the BBB; endogenous signals in gall bladder, intestine, and organs involved in clearance	32,43
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)	369	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 the BBB; some tracers clinically approved; 68Ga/111In-based tracers are readily accessible	44, 45, 46, 47
	dopamine receptor (D2R)	G protein-coupled receptor; high endogenous expression in pituitary gland and striatum	443	PET: [18F]FESP, [11C]raclopride, [11C]N-methylspiperone	slow clearance of [18F]FESP; tracers cross the BBB	48, 49, 50, 51
	transferrin receptor (TfR)	fast recycling receptor	760	MRI: transferrin-conjugated SPIO	transferrin-conjugated SPIO particles are internalized by cells	52
Cell surface protein	glutamate carboxy-peptidase 2 (PSMA) and variant tPSMAN9Del	tPSMAN9Del has higher plasma membrane concentration; high expression in prostate	750	PET: [18F]DCFPyL, [18F]DCFBC; SPECT: [125I]DCFPyLb; anti-PSMA antibodies and ligands can be flexibly labeleda; e.g., J951-IR800	background signal in kidneys; tracers do not cross the BBB; ome tracers clinically approved	28,29
Cell surface-antigen	human carcinoembryonic antigen-based reporters	CEA expressed in pancreatic, gastric, colorectal, and medullary thyroid cancers; reporters are recombinant proteins based on CEA minigene (N-A3) fused to extracellular and transmembrane domains of human FcγRIIb receptor, CD5, or TfR carboxyl-terminal domain	ca. 460	PET: 124I-anti-CEA scFv-Fc H310A,b [18F]FB-T84.66 diabody; SPECT: 99mTc-anti-CEA Fab′, 111In-ZCE-025, 111In-anti-CEA F023C5ic	tracers do not cross the BBB; 99mTc-anti-CEA Fab′ is clinically approved	53,54,55, 56, 57
Artificial cell surface molecule	DOTA antibody reporter 1 (DAbR1)	scFv of murine anti-DOTA IgG1 antibody 2D12.5/G54C fused to human IgG4 CH2-CH3 and the transmembrane domain of human CD4	ca. 470	PET: 86Y-AABD	86Y-AABD is a DOTA complex that binds irreversibly to a cysteine of 2D12.5/G54C; tracer does not cross the BBB	58
	estrogen receptor α ligand binding domain (hERL)	no reported physiological function; endogenous estrogen receptor expression limited to uterus, ovaries, and mammary glands	estimate250d	PET: [18F]FES	tracer is clinically used estrogen receptor imaging agent; imaging agent crosses the BBB	30
	anti-PEG Fab fragment	recombinant protein with N-terminal hemagglutinin (HA)-tag, anti-PEG Fab, followed by a c-myc epitope and eB7; tags could cause immunogenicity	812	PET: 124I-PEG-SHPPb,c; MRI: SPIO-PEG; fluorescence, e.g., NIR797-PEG	iodine tracers bear risk of deiodination; some tracers cross the BBB; PEG is non-toxic and approved by the US Food and Drug Administration (FDA)	59
Carrier protein	ferritin	human heavy and light chains co-expressed, or murine heavy chain only expressed as reporter	Hu: 183/175	MRI: iron	iron is not equally distributed across the brain and therefore may cause local susceptibility shifts that are above the MRI detection limit	60,61

Promise was evaluated by the authors based on (1) human reporter origin ensuring no immunogenicity against the therapeutic cells expressing the reporter, and (2) availability of at least one already clinically approved or first-in-man tried labeling agent.

^aAmino acid chain length as an indication of reporter molecular weight (MW; not accounting for posttranslational modifications); wild-type reporter MWs are indicated.

^bRadioiodinated tracers can become de-iodinated in vivo, resulting in free iodide that is subsequently taken up into NIS-expressing organs.

^cAny other modality can be used provided a suitable contrast-forming moiety will be attached to PEG and the CEA antibodies, respectively.

^dReport³⁰ does not clearly describe reporter construction, leaving precise reporter size only to be estimated; we estimate it based on the estrogen receptor α ligand binding domain, which is approximately 250 aa long (cf. http://pfam.xfam.org/family/PF02159).