Targeted PET/MRI Imaging Super Probes: A Critical Review of Opportunities and Challenges

Figures & data

Figure 1 Graphical representation of the principle of the MRI and PET techniques.

Figure 2 Solvent molecules (H₂O) and the Fe(III) and N-methylacetohydroxamate (NMA^–) complex, as well as the specific chemical interactions. The ORTEP view [source: Mercury program 3.10.1 (Build 168220).] of the [Fe(NMA)₃] crystal structure²² was generated using atomic coordinates taken from the CSD database (structure code: CCDC 1538337).

Figure 3 RIME (receptor-induced magnetization enhancement) effect.

Figure 4 Ideological presentation of an MRI/PET probe based on chelated radionuclides (metal complex for PET imaging) and superparamagnetic iron oxides (SPION for MRI contrast).

Table 1 Relaxivity of MRI Contrast Agents

Entry	r1	r1	r2	r2	B0	t [̊C]	Paramagnet Content [%]	Size [nm]	Remark, Ref.
	mM^−1s^−1	(mg/mL)^−1s^−1	mM^−1s^−1	(mg/mL)^−1s^−1	[T]
Discrete complexes
GdDOTA-4AMP-F	7.4–3.9	10–19			1.4	37	14% (Mw)		[^Citation40]
Gd-NPep-Fl (MRI or PET probe)	21.2	16			1.4	37	12% (Mw)		[^Citation41]
[GdDO3A-SA–Ga(AAZTA)]^−	3.7–10.1	9–24			0.47	25	13% (Mw)		[^Citation42]
Gd-PCTA-Lys(ZW800–1)-OAl	5.47	6			9.4	37	18% (Mw)	0.31	[^Citation43]
Nanoparticles (NP)
Commercial SPIONs
Feridex^®	23.9		151.9		3	20		80–150	[^Citation36,^Citation44]
Feraheme^TM (ferumoxytol)	10	75	89	667	4.7; 3	37	41.21% Fe	17–35 nm	[^Citation45,^Citation46]
New hybrids
MnMEIO			321.6	4400	1.5		75.25 Mn+Fe %	32 (hydro)	[^Citation37]
Jarrett2008-ADIO	14.46	129	72.55	659	1.4	37	50%	32.3	[^Citation47]
Lee2008-PASP-IO			105.5	2134	3	20	72.3% (X-ray Fe3O4)	45±10	[^Citation36]
DOTA-mSPIO			209		0.47			20.3 (hydro)	[^Citation48]
EP-2104R	41				3		Gd 100000 Da protein		[^Citation41]
SPIO_cRGD			101.9	204	4.7	18	11.2%Fe	10	[^Citation49]
CAN-Magh	0.2	2	72	601	V1.5		64.4% Fe	44–55(hydro)	[^Citation50]
DIO/Cu	17.1		135.8		1.4	37		45.7	[^Citation51]
NOTA–OA–IONP			157		4.7			66	[^Citation34]
SPION@PAA			93.8		4.7	37			[^Citation35,^Citation52]
PEM			265.0	261	3		5.5%Fe	140	[^Citation23]
Fe3O4@Al(OH)3	3.7	49	121.9	279	3		7.92	49.8	[^Citation53]
SDIO	18.1	36	95.8	194	1.4	37	11.34%Fe	62.4	[^Citation39]
DIO	15.7	49	89.2	279	1.4	37	17.53%Fe	38.1	[^Citation39]
AGuIX	10.3		13.4		1.4		12.42% (ICP-MS)	2.5 (hydro)	[^Citation54]
NOTA-IO-Man			449.9					10.12 (hydro)	[^Citation55]
DOTA-IO-GUL			185		9.4			11.01	[^Citation56]
68Ga-C-IONP	5.7	51.7	22.2	201.3	1.5	37	50.6% Fe	20.6	[^Citation57]
s-SPION25			953		11.7	rt		25	[^Citation58]
NPs-dopa-PEG-DOTA/RGD			267.5	1609	7.0		32.5%Mn&Fe	26.4	[^Citation38]
NOTA−FA−FI−PEG−PEI−Ac−Mn3O4	0.57	4.04			0.5	37	40% Mn	476.5 (hydro)	[^Citation59]
AGuIX	13.5	12	18.2	16	1.4	37	14% Gd (Mw)	4.6	[^Citation60]
SPION−LDOPA−PEG−MANOTA			360	3965	3		61.5% Fe	119	[^Citation60]
FH	10–20		57–60						[^Citation61]
Au-Fe3O4@PDA-PEG-DTPA-Gd T1/T2/ dual model	6.14		71.88		3.0		22800 Gd/NP	70.89	[^Citation62]

Table 2 PET Isotopes and Their Half-Lives

Isotope	^11C	^68Ga	^18F	^64Cu	^69Ge	^89Zr	^124I
Half-life	20.4 min	68 min	110 min	12.7 h	39.5 h	78 h	100 h

Table 3 PET/MRI Bimodal Probes

Molecule	Isotope	Paramagnetic	Activity per Inj.	Dose	Target (Targeting Vector)	Accumulation^a	Clearance^b	Ref
Liposome	^89Zr	Gd	35–40μCi	2.78 μmol Gd-DTPA-BiSA	Neuroendocrine tumor: SSTr2-postive transduced cell (OCT)	RES – 18% ID/g Bones – 12% ID/g Tumor – 3.5–5%ID/g @ 50 h pi	>96 h through RES	[^Citation45]
PLGA/PEG	^64Cu	SPION	100 μCi	0.1 mg SPION	Breast tumor	Tumor - 3.5 ± 0.25% ID/g Liver 22.0 ± 6.0% ID/g Spleen, kidneys - 5% each @ 20 h pi	50 h (from blood) Renal excretion of ^64Cu	[^Citation23]
FH	^89Zr	SPION	185–195 μCi	~0.20–0.21 mg Fe	Muscle inflammation	Inflamed muscle - 0.95–0.12%ID/g Liver - 101.93%ID/g Spleen 132.96%ID/g @ 120 h pi Inflamed-to-control muscle ratio at 120 h pi: 9.64 ±2.49	>120h	[^Citation67]
PAA modified SPIONs	^69Ge	SPION	50 µCi 10 µCi (paw inj.)	7.77 mM Fe	SLN	Liver - 13%ID/g Spleen 9%ID/g @ 36 h pi SLN – 28%ID/g (paw inj.) @ 20h pi	>36 h	[^Citation52]
PAA modified SPIONs	*As	SPION	148.5 µCi 81 µCi (paw inj.)	40 μL, 7.77 mM of Fe	SLN	Liver - 25 and 11%ID/g Bladder - 12 and 3.8%ID/g @0.5 h and 20 h pi SLN 12.5 and 13.2%ID/g (paw inj.) @ 2.5 and 15 h pi	No data	[^Citation35]
MnMEIO	^124I	MnFe2O4,	110 µCi 335 μCi (paw inj.)	80 µg (Mn+Fe inj.) 229 mg/kg (Mn+Fe)	SLN	No data	> 144 h	[^Citation37]
MnFe2O4 and Fe3O4	^18F	Fe	25 µCi	60 mg Fe				[^Citation53]
NOTA-FA-PEG-PEI-Ac-Mn3O4	^64Cu	Mn3O4	200 μCi	2.5 mg/mL, inj. 200 µL	Folate receptor in cervical cancer (folic acid)	Tumor - 1.5%ID/g Liver 6%ID/g Kidneys, spleen ~2.5%ID/g @ 24h pi Tumor-to-muscle ratio: 5.35 ± 0.31 at 18 h	>24 h	[^Citation59]
PEGylated phospholipids	^64Cu	SPION	100 μCi	10 mg Fe/kg body weight		Liver, spleen – 31± 18%ID/g @ 1h pi	>24h	[^Citation48]
Cu-Dota/ Dextran coated SPION	^64Cu	SPION Gd	20–25 µCi/g	18–20 mg Fe/kg	Vascular inflammation/receptor SR-A (Mal-BSA)		>24 h	[^Citation39,^Citation45,^Citation97]
SPION-NOTA-Ga	^68Ga	SPION	100 µCi	1 mg/mL of IONP or OAeIONP	Colon cancer cells (oleanic acid)	Tumor 3.07 ± 0.76%ID/g Liver – biggest uptake @ 1h pi	>4h	[^Citation33]
DOTA-RGD-PASP	^64Cu	SPION	100 µCi	300 µg Fe	Integrin αvβ3 (RGD)	Tumor - 10.1 ± 2.1%ID/g Liver - 22.6 ± 2.9%ID/g Kidneys - 4.9 ± 0.8%ID/g @ 4 h pi	>4h	[^Citation36]
PEGylated MnFe2O4	^64Cu	MnFe2O4	100 μCi	200 μg Fe	Integrin αvβ3 (RGD)	Liver - 27%ID/g Spleen - 8%ID/g Kidneys - 7%ID/g Tumor- 6%ID/g @ 6h pi	>6h	[^Citation38]
PEG-PLGA- SPION	^68Ga	SPION	200 ± 64.8 µCi	3.8 ± 1.3 μg of Fe2O3	Pancreatic ductal adenocarcinoma	Liver - 1.7%ID/g Spleen - 2.1% ID/g @ >20 min pi	No data	[^Citation50]
DOTA-GUL	^68Ga	SPION	275.4 µCi	200 μM DOTA-IO-GUL	Prostate (PSMA - GUL)	Tumor specificity	No data	[^Citation56]
TRAP(HMDA–DOTA)	^68Ga	Gd	727 µCi	130 mg/kg		Kidneys @ 25 min pi	No data	[^Citation71]
Dextran coated SPION	^68Ga	SPION	405 µCi	0.11mg Fe	Melanoma (RGD)	Tumor, heart – 9%ID/g each Spleen, kidneys 10%ID/g Liver - 25%ID/g	No data	[^Citation57]
BP-based 64Cu-(dtcbp)2 and dextran-coated SPION	^64Cu	SPION	54 µCi	44 mg Fe	SLN	SLN	No data	[^Citation68]
–COOH and –NH2 functionalized SPION	^11C	SPION	100 μCi			Liver	> 5 h	[^Citation72]
Silicone-DOTAGA-Gd	^64Cu ^68Ga	Gd	270 µCi			Kidneys - 35%ID/g Liver - 15%ID/g Spleen - 5%ID/g Tumor - 2%ID/g @ 24 h pi	>24h Renal + hepatic clearance	[^Citation60]
LDOPA-PEG-MANOTA	^64Cu	SPION	67.5–100 μCi	0.8−1.2 μmol Fe		Liver - 9%ID/g Lungs, spleen- 6% ID/g each Kidneys 5% ID/g @ 48h pi	> 48 h	[^Citation66]
DOTAGA-Gd + NODAGA-Ga	^68Ga	Gd	25 µCi	20 μmol AGuIX		Kidneys, bladder	> 2h	[^Citation54]
^89Zr-DFO-labelled ferumoxytol	^89Zr	SPION	35 µCi	0.25 mg Fe	Tumor-draining lymph nodes, prostate	Liver – 23%ID/g Lymph nodes >40% ID/g @ 24 h pi	>48 h	[^Citation45]
EP-2104R (DOTA)	^64Cu	Gd	530 ± 186 µCi	46 mmol Gd per kg	Fibrin, (six amino-acid cyclic peptide)		>2h	[^Citation41,^Citation98]
DOX conjugated SPION	^64Cu	SPION	135–270 µCi		Integrin αvβ3 (RGD)	Tumor 5.6 ± 1.7%ID/g Liver 9.7± 2.7%ID/g @ 6 h pi	>48h	[^Citation49]
NOTA-IO-Man	^68Ga	SPION	324 µCi		SLN (Man-SA)	SLN accumulation	No data	[^Citation55]
Gadofullerene-PEG-RGD	^68Ga, ^89Zr	Gd	432 µCi	20 µmol Gd	Integrin αvβ3 (RGD)	Tumor 2.4 ± 0.2%ID/g @48 h pi	>720h	[^Citation95]
^89Zr-DFO-RGD-BSA-SPION	^89Zr	SPION	1 mCi		Integrin αvβ3 (RGD)	Tumor 1.5%ID/g Liver 22%ID/g @72 h pi	>72h	[^Citation64]
Melanin-apoferritin	^64Cu	Fe	100 µCi	10 nmol of NP	Colon cancer cells (TfR1)	Tumor 7.34 ± 0.93%ID/g @4 h pi	>26h	[^Citation65]

Notes: ^a@ X h pi = at X hours post-injection. ^b> “X” means, that biodistribution or accumulation data is available only to certain time post-injection. *71, 72, 74, 76.

Table 4 Doses of Bimodal Probes Injected in vivo Compared with the Amounts Tested for Cytotoxicity in vitro

Bimodal Probe	Injected in vivo	Tested in vitro	Ref.
64Cu-USPIO-PLGA	0.73 µg Fe/mL	3.35–15 µg Fe/mL	[^Citation23]
Fe3O4− LDOPA−PEG−MANOTA−64Cu	0.8–1.2 µmol Fe (74–111 µg SPION*)	0.3 mg Fe/mL	[^Citation66]
Magh-1-PNPs-NODA	3.8 µg Fe in 300 µL (12.8 µg/mL)	3–6 µg Fe	[^Citation50]
68Ga-C-IONP	1.1 mg Fe/mL	100 µg Fe/mL	[^Citation57]
68Ga-NOTA-OA-IONP	1 mg IONP/mL	0.5–512 mM IONP	[^Citation34]
68Ga-AGuIX	Not injected	3 mM Fe	[^Citation58]

Note: *Calculated based on TGA.

Figure 5 Ratios (R) of labeling time/half-life and the radiochemical yields of some reported bimodal probes. R was counted for probes with a known labeling time.

Table 5 Bioresponsive Characteristics of MRI/PET Probes

Probe	Stimulus, Range	Effect MRI Relaxivity, PET Signal	Ref
Furallo2010-GdDOTA-4AMP-F	pH 6–8	r1 6–8 mmol^−1s^−1 in vitro	[^Citation40]
Vologdin2013-[GdDO3A-SAGa(AAZTA)]	pH 6v8	r1 4–10 mmol^−1s^−1 in vitro	[^Citation42]
Notni2013- TRAP(HMDA–DOTA)3	Temp. 25/37 °C	r1 5.69/4.73 (7 T) or 7.06/5.69 mmol^−1s^−1 (0.5 T)	[^Citation71]
Yang2011	pH 5.3/7.4	Drug (doxorubicin) release	[^Citation49]

Table 6 Main Features of Classic Complexes and Nanoparticles as Potential MRI-PET Bimodal Probes

	Discrete Complexes	Nanoparticles
Visual effect in MRI	Brightening, no general drawbacks	Darkening, may hamper discrimination from bulk, artifacts overlap, first reports as T1/T2 dual CAs
Preparation	Rapid, selective	Might be even more rapid, often chelator free
Size	< 1 nm	20–140 nm
Clearance	Kidney (as long as r<5.5 nm)	Absorbed by the reticuloendothelial system in the liver and spleen
Targeting	Intercellular and intracellular	Intercellular, vascular system
Advantages	Large experience based on hitherto applications – known pharmacokinetics, clearance, possible bioresponsive characteristics, higher flexibility in targeting	Great potential in parallel drug delivery and theranostic functions
Drawbacks	Limited control over the paramagnet/radionuclide ratio desired for good performance of both modalities; Radiolabelling might be not selective	Limited permeability due to size Fears of deposition Poor MRI contrast Potentially lower bioresponsive characteristics

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