CA2805543C - Porphyrin compounds and their use as mri contrast agents - Google Patents

Abstract

Water soluble porphyrin compounds useful in the field of magnetic resonance imaging (MRl) as contrast agents. Particular compounds include manganese.

Description

Porphyrin Compounds and Their use as MRI Contrast Agents FIELD OF THE INVENTION
The present invention relates to water soluble porphyrin compounds useful in the field of magnetic resonance imaging (MRI) as contrast agents.
BACKGROUND OF THE INVENTION
Developed in the 1970'0, MRI has rapidly grown into an indispensable and increasingly popular imaging modality. Owing to its deep tissue penetration, non-invasiveness, excellent soft tissue contrast and high spatial resolution, MRI
is used for diagnosis and treatment monitoring of a wide variety of diseases.
In conventional MRI scans, signals are mainly derived from 1H-NMR peaks of water and fat molecules present in the body being imaged. The image contrast of the tissues is determined by a number of factors, such as proton density, spin-lattice relaxation time (T1), and the spin-spin relaxation time (12). Ti is a measure of how quickly the longitudinal magnetization vector (Me) of spinning nuclei recovers towards the equilibrium direction after a resonant radio frequency (RF) pulse6. T2 relaxation time is a time constant that describes the dephasing of the transverse nuclear magnetization.
Since Ti and T2 relaxations vary from tissue to tissue, acquisition parameters can be adjusted to differentiate among tissues. For example, dipoles in fats or hydrocarbon rich environments have much shorter T1 relaxation times than those in aqueous environments.
Despite its increasing number of applications, MRI is impeded by its intrinsic low detection sensitivitP compared to imaging modalities that use ionizing radiation such as Positron Emission Tomography (PET), hampering its ability to detect certain pathologies, such as small tumors or differentiating post therapy tumor progression.
Governed by the thermal equilibrium polarization of the nuclei, e.g. at room temperature and magnetic field of 1.5 Tesla (T) (commonly used in most clinical MR
scanners), only 5 out of 1 million 1H spins are polarized9. According to Curie's Law, macroscopic magnetization is directly proportional to the magnetic field strength10.
Increasing the field strength can partly compensates for this loss in sensitivity and improve signal-to-noise ratio (S/N)11. However, other than the cost of ultrahigh field scanners (higher than 7 T), there is a major concern relating to tissue overheating due to overexposure of radiofrequency12 and technical issues such as coil design13.
Currently, the widely applied method of increasing MRI SIN, hence contrast and specificity, is the use of relaxation contrast agents, which can accelerate the relaxation rate of surrounding waters' nuclei spins. MR1 CAs are categorized into Ti and T2 agents.
Ti agents are mainly based on paramagnetic metal ions with unpaired valence electrons which can effectively shorten mainly the T1 relaxation time of the nearby water nuclei via electron-nuclear spin-spin coupling6. Clinical Ti CAs predominantly utilize Gd(III) which is chelated by different ligands to reduce the toxicity of free Gd(III) in vivo.
Typical ligands include diethylene-triamine-penta-acetic acid (DTPA; Gd-DTPA
is sold under the name Magnevist ) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA; Gd-DOTA is sold under the name Dotarem ) and their derivatives.

agents, which are mostly superparamagnetic particles, disrupt the homogeneity of the magnetic field causing predominant decreases in T2 and 12* due to diffusion of water through field gradients. Ti agents are able to generate positive contrast (increased signal intensity) in T1 weighted images while T2 agents such as superparamagnetic iron oxide nanoparticles (SPIONs), generate negative contrast in T2 weighted images. For clinical diagnostic applications, T1 agents are usually preferred because a number of natural sources (tissues with low signal intensity) also generate negative contrast, complicating the analysis of the MRI image. In fact, most FDA approved 12 agents were discontinued. Therefore the focus of this patent is on Ti agents.
A number of Gd-based CAs have been approved for clinical applications, such as ProHance and Magnevist , which are currently dominating the CA market. At least two problems exist with small Gd-based CAs. The relaxivity of Gd-based contrast agents could be higher, particularly at high magnetic fields e.g., at 3 T or higher.
Further there is a problem of toxicity that results from free Gd(III) i.e., which escapes the chelating agent in certain patients with renal dysfunction. These two issues are interrelated.
Small Gd-based CAs have relatively low relaxivity (about 3-4 mtV1-1s-1 at 1 T, 37 C) and as a result, gram quantities are typically injected into a patient for generating

- 2 -an image with reasonable quality. In recent years, MRI scanners are moving to higher magnetic fields (mainly 3 T) in order to perform scans with improved signal/noise ratio, shorter acquisition times and better image resolution. Since the relaxivity of the commercially available Gd-based CAs decreases at higher magnetic fields, even larger quantities of CAs would be required for adequate contrast enhancement14. In addition, studies such as contrast-enhanced MR angiography and delayed contrast-enhanced myocardinal viability examinations require even higher CA doses and thus, further increase the risk of metal toxicity15. Although many in vitro studies have indicated that these Gd-based CAs are thermodynamically stable, the emergence and proliferation of nephrogenic systemic fibrosis (NSF) cases correlated to the usage of Gd-based CAs since the late 1990s suggests in vivo release and accumulation of toxic free Gd(III) in certain patients with renal dysfunction. Symptoms of NSF include severe skin induration, muscle restlessness and sometimes, physical disability. To address the severity of this safety issue, the FDA requires a "Black Box" warning label to be attached to all Gd-based CAs indicating possible adverse effects.
Various attempts have been made to improve the relaxivity mainly by Increasing the size and thus rotational diffusion time (TR) of Gd-based CAs, based on the Solomon-Bloembergen-Morgan (SBM) theory. Common strategies include attachment of Gd CAs to proteins, dendrimers or polymers. Notably, at high magnetic fields (>1.5 T), the electron spin relaxation of Gd(III) dominates the inner-sphere relaxivity, therefore, the strategy of increasing TR becomes much less efficient to improve ri for Gd-based CAs at high fields than low fields. Despite the moderate relaxivity increase, Gd toxicity is likely to persist In these macromolecular CAs16. In fact, because most of the conjugation chemistry involves the chelation sites, the Gd affinity will be lowered, contributing to higher risk of heavy metal leakage. In addition, the internal flexibility of these aliphatic dendrimers or polymers also contributed to the less than expected increase in relaxivity per Gd. Lastly, these large CAs are retained in the body for a longer period of time, leading to higher chance of Gd release than small Gd-based CAs.
There is thus a need to create a new generation of As that is more efficient and avoids the adverse effects of Gd toxicity. It will be desirable if the new generation of -.3-CAs are free of toxic heavy metals such as Gd(III)and exhibit high Tlrelaxivity at high field.
SUMMARY
The invention includes a water soluble porphyrin compound of formula (A), or a salt thereof:
\N N"--\
NN' /
G Ft' (A) wherein one or more of D, E and F is defined as in paragraphs (a) to (c):
(a) (i) D is of the formula (LD):
=,. =
R \
\N \N
/
L0' \ /14\

N\ N N
Ft= / Wow N. Ra4 R. Dz (LD) wherein:
each LD and LDI is independently a covalent bond or a rigid bivalent linker;
one or the other or both of DI and D2 is a water-solubilizing group;
one or more of D3, D4 and Ds is a water-solubilizing group; and mD has a value of from 0 to 20; or (ii) D is of the formula (LW):

Rss = l=
= 134 R,' N
IN====¨"Li¨ N I
/ I \
R??
.===,"
= it -Lo?
Rss "

/ I \
R,4 R. "
Lo\
Los \ Ds R. 23 4.47.44. N

-=5 FrP?
Los Rs, " Dia Rs? \
, ,,,r_N, , Rss Rss Ds D, (LD') wherein:
LD is a rigid trivalent linker;
each LD1 is, independently of any other 1. 1, a covalent bond or a rigid bivalent linker;
each LD2 is, independently of any other 1.1)2, a covalent bond or a rigid bivalent linker;

each 03 is, independently of any other L 3, a covalent bond or a rigid bivalent linker;
each L 4 is, independently of any other 04, a covalent bond or a rigid bivalent linker;
one or the other or both of D1 and D2 is a water-solubilizing group;
one or more of D3, D4 and D6 is a water-solubilizing group;
one or the other or both of D6 and DT is a water-solubilizing group;
one or more of 1)8, 03 and D1 is a water-solubilizing group;
MD1 has a value of from 0 to 20; and mD2 has a value of from 0 to 20;
(b) (I) E is of the formula (LE):

R R.+ R fta N N N
\ NK / / \ N N X /
N
R . \I / Raft \I
R4e E, All R" El R" (LE) wherein:
each LE and LE.' is, independently, a covalent bond or a rigid bivalent linker;
one or the other or both of E1 and E2 is a water-solubilizing group;
one or more of E3, E4 and E3 is a water-solubilizing group;
mE has a value of from 0 to 20; or (ii) E Is of the formula (LE'):

E.
R63 / \
R.
N I
/ I \

fi*
mf R5 Fi15 \ = t2 I N I
/ \
R. R4, R." R.
.""'" LE\ to E, Rez R11 -E=
m" Is4 Fin "
Ro* N
R.15 I N N I

R>, (LE') wherein:
LE is a rigid trivalent linker;
each LEI is, independently of any other LEI, a covalent bond or a rigid bivalent linker;
each LE2 is, independently of any other LE2, a covalent bond or a rigid bivalent linker;

each LE3 is, independently of any other Lc3, a covalent bond or a rigid bivalent linker;
each LE4 is, independently of any other LE4, a covalent bond or a rigid bivalent linker;
one or the other or both of El and E2 is a water-solubilizing group;
one or more of E3, E4 and E is a water-solubilizing group;
one or the other or both of E6 and E7 is a water-solubilizing group;
one or more of E8, E and El is a water-solubilizing group;
mEl has a value of from 0 to 20; and mE2 has a value of from 0 to 20;
(c) (i) F is of the formula (LF):
Rtt F' /4 12.3 = t4 \ R" Ng, \ N W====== \ N
IF
\ X /
X N N i+1 N
RI4R \ .0" / "
p p (LF) wherein:
each LF and LFI is, independently, a covalent bond or a rigid bivalent 16 linker;
one or the other or both of Fl and F2 is a water-solubilizing group;
one or more of F3, F4 and F6 is a water-solubilizing group;
L" Is a covalent bond or a rigid bivalent linker; and mE has a value of from 0 to 20; or (ii) F is of the formula (IF'):

-.4 = oi jr Res / \
Roo N I
/ I \
Rot RAI

Fo " Ro7 MTh I N I
/ I \
Rio fln ¨
X== = a = 01 P
Roo IN.===¨"M=¨= N I
/ I \
Re4 Roo ""=====.
= no rrtz R" N Po Rol N
Re' R,o2 Roo Fo Fo Ries Fttor (LF') wherein:
LF is a rigid trivalent linker;
each LF1 is, independently of any other LFI, a covalent bond or a rigid 6 bivalent linker;
each LF2 is, independently of any other LF2, a covalent bond or a rigid bivalent linker;

each I-F3 is, independently of any other LF3, a covalent bond or a rigid bivalent linker;
each LF4 is, independently of any other LF4, a covalent bond or a rigid bivalent linker;
one or the other or both of F1 and F2 is a water-solubilizing group;
one or more of F3, F4 and F5 is a water-solubilizing group;
one or the other or both of Fe and F7 is a water-solubilizing group;
one or more of F8, F9 and F19 is a water-solubilizing group;
mF1 has a value of from 0 to 20; and has a value of from 0 to 20; and wherein:
when D, E and F are all defined as in paragraphs (a) to (c), G is a water-solubilizing group, or G is defined as in paragraph (d):
(d) (i) G is of the formula (LG):
.õ, G. = 114 R \ RIOS " RIO
N N
( Le \ < L
N N N N

..õe R",,, R1,0 R", R"0 60 Rim (LG) wherein:
each L and 01 is, independently, a covalent bond or a rigid bivalent liner;
one of the other or both of G1 and G2 is a water-solubilizing group;
one or more of G3, G4 and G5 is a water-solubilizing group;
LG1 is a covalent bond or a rigid bivalent linker; and m has a value of from 0 to 20; or (ii) G is of the formula (LG.):

ri, I N I
\
mei R.
No. 1 N I

R
R" GI

G, Fo$ N
.132 R. f .132 171" ISA
R122 R4. Gio Ro3 N
-I N\ I
it I
RI$4 F1',0 Go Ri3s Roe wherein:
19 is a rigid trivalent linker;
each 191 is, independently of any other 191, a covalent bond or a rigid bivalent linker;
each L.G2 is, independently of any other LG2, a covalent bond or a rigid bivalent linker;

each 03 is, independently of any other 03, a covalent bond or a rigid bivalent linker;
each 04 is, independently of any other 04, a covalent bond or a rigid bivalent linker;
one or the other or both of G1 and G2 is a water-solubilizing group;
one or more of G3, G4 and G5 is a water-solubilizing group;
one or the other or both of G6 and G7 is a water-solubilizing group;
one or more of G8, G6 and Gi is a water-solubilizing group;
mG1 has a value of from 0 to 20; and mG2 has a value of from 0 to 20; and the sum of m13, m1)1, mD2, mE, mEl, mE2, mF mF1, mF2, mG, -G1 m and IT1G2 is from 0 to 30;
and M is a paramagnetic metal ion present in at least one porphyrin ring, and may be the same or different when present in a plurality of porphyrin rings.
In embodiments of a compound having formula (A), G can be a water-solubilizing group selected from:
(I) carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03R1-1), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-N R3), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2, a C3-C20 cycloalkyl group containing a nitrogen atom in its ring wherein the cycloalkyl group is bonded to the porphyrin ring by a carbon or nitrogen atom, a C3-C20 aryl group containing a nitrogen atom in its ring, and OH
V
14, OH

wherein n is from 1 to 20;
C1-C20 alkyl substituted with one or more of sulfonate, phosphate (-0P031-12).

alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P021-J), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=CI);
C3-C20 cycloalkyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03F12), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 heterocycloalkyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thin!, cyano, nitro, oxo (=0);
alkenyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR34), aminoalkyl ((C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);

C3-C20 cycloalkenyl substituted with one or more of sulfonate, phosphate (-0P03112), alkylphosphate (-0P03RH), phosphonate (-P031-12), alkylphosphonate (-P03RH), phosphinate (-P021-1), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 heterocycloalkenyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalky (-(C1-C20 alkyl)NH2)I, guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
Cg to C20 aryl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03112), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro;
C3 to C20 heteroaryl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro;
to C20 arylalkyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P031-12), alkylphosphonate (-P03R1-I), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C4 to C20 heteroaryialkyl substituted with one or more sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR34), aminoalkyl (-(C 4-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C2 to C20 alkynyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03112), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C1 to C20 heteroalkyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03112), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C2 to C20 heteroalkenyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0); and C2 to C20 heteroalkynyl substituted with one or more of sulfonate, phosphate (-0PO4-12), alkylphosphate (-0P03RH), phosphonate (-P03F12), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0), wherein each R is independently straight or branched C1-C20 alkyl;
In such embodiments, one or more of i.e., at least one of D, E and F can be defined as in foregoing paragraphs (a) to (c) in which:
(A) the one or the other or both of 01 and 02 that is a water-solubilizing group is, independently of the other, as defined in paragraph (I), and the other of D1 and D2 is selected from the group consisting of:
(II) hydrogen;
C1-C20 alkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 cycloalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 heterocycloalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
Ci-C20 alkenyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 cycloalkenyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 heterocycloalkenyi optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);

C6 to C20 aryl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro;
C3 to C20 heteroaryl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro;
C7 to C20 arylalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C4 to 020 heteroarylalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C2 to 020 alkynyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C1 to 020 heteroalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C2 to C20 heteroalkenyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C2 to C20 heteroalkynyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
(B) the one or more of D3, D4 and D5 that is a water-solubilizing group is, independently of the others, as defined in paragraph (I), and the other of D3, and D5 is, independently of the others, as defined in paragraph (II);
(C) the one or the other or both of D6 and D7 that is a water-solubilizing group is, independently of the other, as defined in paragraph (I), and the other of D6 and D7 is, independently of the others, as defined in paragraph (II);
(D) the one or the other or both of El and E2 that is a water-solubilizing group is, independently of the other, as defined in paragraph (I), and the other of El and E2 is, independently of the others, as defined in paragraph (II);
(E) the one or more of E3, El and E5 that is a water-solubilizing group is, independently of the others, as defined in paragraph (I), and the other of E3, and E5 is, independently of the others, as defined in paragraph (II);

(F) the one or the other or both of E6 and E7 that is a water-solubilizing group is, independently of the other, as defined in paragraph (I), and the other of E6 and E7 is, independently of the others, as defined in paragraph (II);
(G) the one or the other or both of F1 and F2 that is a water-solubilizing group is, independently of the other, as defined in paragraph (I), and the other of F1 and F2 is, independently of the others, as defined in paragraph (II);
(H) the one or more of F3, F4 and F5 that is a water-solubilizing group is, independently of the others, as defined in paragraph (I), and the other of F3, and F5 is, independently of the others, as defined in paragraph (II);
(I) the one or the other or both of F6 and F7 that is a water-solubilizing group is, independently of the other, as defined in paragraph (I), and the other of F6 and F7 is, independently of the others, as defined in paragraph (II); and the other(s) of said one or more of D, E and F can be as defined in paragraph (I) or (II);
and each of R1 to R107 can be, independently of the others, as defined in paragraph (I) or paragraph (II).
In particular embodiments, each said rigid bivalent linker is, independently, selected from the group consisting of:
, , ¨"X

3 /""14 , (X, - 0, S (X, V. Z 0, or 1=111) s 20 wherein a said linker is optionally substituted with one or more water-solubilising groups and a said linker is optionally substituted with one or more of the substituents defined by paragraph (II). It is preferred that the one or more water-solubilising groups with which such a linker is optionally substituted is selected from the group defined by foregoing paragraph (I).
In such embodiments, each of E and F can be, independently of the other, a 6 water-solubilizing group selected from:
carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR31.), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2, a C3-C20 cycloalkyl group containing a nitrogen atom in its ring wherein the cycloalkyl group is bonded to the porphyrin ring by a carbon or nitrogen atom, a C3-C20 aryl group containing a nitrogen atom in its ring, and o 0 OH
Oli wherein n is from 1 to 20, and each R is independently straight or branched Cl"
C20 alkyl; and D can be of the formula (LD) wherein m has a value from 0 to 10.
According to particular embodiments of the compound, or a salt thereof, each L

and L 1 is a covalent bond, , Or =
each of D1, D2, D3, D- 5 , E, F and G is p-sulfonated phenyl or carboxyl;
each of R1 to R24 is H;
m is 8; and and M is manganese for each porphyrin ring.
In a particular embodiment of the compound, or a salt thereof, D is of the formula (LO);
mD = 0;
01 is:
/
each of D3, D4, 05, E, F and G is p-sulfonated phenyl;
each of R*1 to R8 and R17 to R24 is H; and each M is manganese.
Other embodiments include a compound, or a salt thereof, wherein D, E, F and G
are as defined as in paragraphs (a) to (d) in which:
(aa) the one or the other or both of 01 and 02 that is a water-solubilizing group is, independently of the other, selected from the group consisting of:
(1) carboxyl, suifonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P021-0, alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR34), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2, a C3-C20 cycloalkyl group containing a nitrogen atom in its ring wherein the cycloalkyl group is bonded to the porphyrin ring by a carbon or nitrogen atom, a C3-C20 aryl group containing a nitrogen atom in its ring, ptc_Lck, .)1-1YH

Off wherein n is from Ito 20;
C1-C20 alkyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkyiphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-MR), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(Ci-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 cycloalkyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P021-1), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylarnino (-NR2), aminoalkyl (-(Ci-C20 alkyl)NH2), guanidine (-NHC(NH)NH2)1 alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 heterocycloalkyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally Substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C1-C20 alkenyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P021-0, alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylarnino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);

C3-C20 cycloalkenyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P031-12), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 heterocycloalkenyi substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C6 to C20 aryl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (4Ci-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro;
C3 to C20 heteroaryl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro;

07 to 020 arylalkyl substituted with one or more of sulfonate, phosphate (-0P03112), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
04 to 020 heteroarylalkyl substituted with one or more sultanate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P021-1), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C2 to 020 alkynyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphwhinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(01-C20 alkyONH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C1 to C20 heteroalkyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate alkylphosphonate (-PO3RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(01-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);

C2 to C20 heteroalkenyl substituted with one or more of sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(Ci-C20 alkyONH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0); and C2 to C20 heteroalkynyl substituted with one or more of suffonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), and optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0), wherein each R is independently straight or branched Ci-C20 alkyl;
(bb) the other of 01 and 02 is selected from the group consisting of:
(2) hydrogen;
Ci-C20 alkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 cycloalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 heterocycloalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
Ci-C20 alkenyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C3-C20 cycloalkenyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);

C3-C20 heterocycloalkenyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
Ce to C20 aryl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro;
C3 to C20 heteroaryl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro;
to C20 arylalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C4 to C20 heteroarylalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C2 to C20 alkynyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C1 to C20 heteroalkyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C2 to C20 heteroalkenyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
C2 to C20 heteroalkynyl optionally substituted with up to 4 of any of hydroxyl, halogen, thiol, cyano, nitro, oxo (=0);
(cc) the one or more of D3, D4 and D5 that is a water-solubilizing group is, independently of the others, as defined in paragraph (1), and the other of D3, D4 and D5 is, independently of the others, as defined in paragraph (2);
(dd) the one or the other or both of De and 07 that is a water-solubilizing group is, independently of the other, as defined in paragraph (1)3 and the other of 06 and D7 is, independently of the others, as defined in paragraph (2);
26 (se) the one or the other or both of El and E2 that is a water-solubilizing group is, Independently of the other, as defined in paragraph (1), and the other of El and E2 is, independently of the others, as defined in paragraph (2);
(if) the one or more of E3, E4 and E5 that is a water-solubilizing group is, independently of the others, as defined in paragraph (1), and the other of E3, E4 and E5 is, independently of the others, as defined in paragraph (2);

(gg) the one or the other or both of E6 and E7 that is a water-solubilizing group is, independently of the other, as defined in paragraph (1), and the other of E5 and E7 is, independently of the others, as defined in paragraph (2);
(hh) the one or the other or both of F1 and F2 that is a water-solubilizing group is, independently of the other, as defined in paragraph (1), and the other of FI
and F2 is, independently of the others, as defined in paragraph (2);
(ii) the one or more of F3, F4 and F5 that is a water-solubilizing group is, independently of the others, as defined in paragraph (1), and the other of F3, F4 and F5 is, independently of the others, as defined in paragraph (2);
Up the one or the other or both of F6 and F7 that is a water-solubilizing group is, independently of the other, as defined in paragraph (1), and the other of F6 and F7 is, independently of the others, as defined in paragraph (2);
(10 the one or the other or both of GI and G2 that is a water-solubilizing group is, independently of the other, as defined in paragraph (1), and the other of GI
and G2 is, independently of the others, as defined in paragraph (2);
(II) the one or more of G3, G4 and G5 that is a water-solubilizing group is, Independently of the others, as defined in paragraph (1), and the other of G3, G4 and G5 is, independently of the others, as defined in paragraph (2); and (mm) the one or the other or both of G5 and G7 that is a water-solubilizing group is, independently of the other, as defined in paragraph (1), and the other of 56 and G7 is, independently of the others, as defined in paragraph (2), and each of RI to R136 is, independently of the others, as defined in paragraph (1) or paragraph (2).
Preferred aspects of such embodiments are compounds or their salts, in which:
D is of the formula (LD'), E is of the formula (LE'), F is of the formula (LP), G is of the formula (LG');
DI 02 ... El E2 Fl F2 Gl G2 .
m - m - m rn mrn rn 1= n1 -0, each of 02, 04, LE2, 04, LF2 LF4, LG2 and I.G4 is a covalent bond, , or ; and each of D3, D4, D5, D8, D9, D10, E3, E4, E5, E8, E9, El , F3, F4, F5, F8, F9, F19, G3, G4, G5, G8, G9 and G19 is p-sulfonated phenyl or carboxyl In a preferred aspect of the compound, or a salt thereof,each of LD, LE, LF
and LG
is:
IP
each of L02, 04, LE2, LE.4, LF2 LF4, L2 and LG4 is:
each of D3, D4, Ds, Da, De, Ea, E4õ Es, Ea, Ea,E10,Fa, F4, Fs, Fa, Fe,F10Ga, G4, Gs, G8, G9 and G19 is p-sulfonated phenyl;
each of RI to R8, R17 to R24, R33. to R40, R49 to R56, R65 to R72, RII3 to R128 and RI29 to R138 is H; and each M is manganese.
A second broad aspect of the invention is a water soluble porphyrin compound of formula (A), or a salt thereof:
R.
N
F D
N
Ft4 \ Re G IV (A) wherein:
each of RI to R8 and D, E, F and G is independently selected from the group consisting of:

hydrogen, halogen, thiol, cyano, nitro, amido (-C(0)NH2), carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR3+), aminoalkyl (-(Ci-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2, a C3-C20 cycloalkyl group containing a nitrogen atom in its ring wherein the cycloalkyl group is bonded to the porphyrin ring by a carbon or nitrogen atom, a C3-C20 aryl group containing a nitrogen atom in its ring, and w 0 H

wherein n is from 1 to 20;
C1-C20 alkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (2=0), carboxyl, sulfonate, phosphate (-0P03112), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2);
C3-C20 cycloalkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=0), carboxyl, sulfonate, phosphate (-0P031-12), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(N11)NH2), alkyl guankline (-NHC(NH)NRH), amido (-C(0)NH2);
C3-C20 heterooycloalkyl, optionally substituted with up to 4 of any of 26 hydroxyl,halogen, thiol, cyano, nitro, oxo (=0) , carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P031-12), alkylphosphonate (-P03RH), phosphinate (-P02H), alkyiphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2);
C1-C20 alkenyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=0) , carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyONH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)N1-12);
C3-C20 cycloalkenyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=0) , carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P031-12)i alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2);
C3-C20 heterocycloalkenyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=0) , carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2);
Ce to C20 aryl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03112), alkylphosphonate (-P03R1-1), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2);
C3 to C20 heteroaryl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C2o alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2);
C7 to C20 arylalkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=0) , carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03112), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 eilkyONH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2);
C4 to C20 heteroarylalkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=0) , carboxyl, sulfonate, phosphate (-0P03H2), alkyiphosphate (-0P03RH), phosphonate (-P03112), alkyiphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyONH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2):
C2 to C20 alkynyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=0) , carboxyl, sultanate, phosphate (-0P03112), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylarnino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyONH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-c(0)N Ho;
Ci to 020 heteroalkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (0), carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P031-12), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-020 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2);
C2 to C20 heteroalkenyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=0), carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2); and C2 to C20 heteroalkynyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=0) , carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P031-12), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2), wherein each R is independently straight or branched C1-C20 alkyl, wherein at least one of R1 to R8 and D, E, F and G is carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03R1-1), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH).
According to an embodiment, each of D, E, F and G is selected from the group consisting of: carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03RH), phosphinate (-P02H), alkylphosphinate (-P02R), amino, alkylamino (-NHR), dialkylamino (-NR2), alkylammonium (-NR34)õ guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and N co 11 ...e"
OH 0 n In preferred aspects,each of D, E, F and G is carboxyl, each of R1 to R8 is hydrogen; and M is manganese. 1 Compounds and salts find use as CAs in MR1. in an aspect, the invention includes a pharmaceutical formulation containing a compound or salt thereof, as described herein. Such a formulation includes a pharmaceutically acceptable carrier, wherein the formulation is suitable for administration as an imaging enhancing agent and the contrast agent is present in an amount sufficient to enhance a magnetic resonance image.
According to another aspect, the invention is a method of generating an image of at least a part of a subject. The method includes administering a compound or salt thereof, as described herein, to a subject, and generating an image of at least a part of said subject to which said compound has been distributed.
According to an embodiment, the invention includes a method of imaging a tumor and surrounding tissue in a subject comprising administering to the subject a composition comprising a compound or salt thereof, as described herein, and imaging the tumor and surrounding tissue in said subject.
The invention includes a composition containing a compound or salt thereof, as described herein, and a pharmaceutically acceptable carrier, excipient or diluent, suitable for administration to a subject.
The invention is also a method for imaging a patient. The method includes administering a composition comprising a compound or salt thereof, as described herein, as a blood-pool imaging agent, and obtaining a magnetic resonance angiography (MRA).
BRIEF DESCRIPTION OF DRAWINGS
Embodiments will now be described, by way of example only, reference being made to the accompanying drawings, in which:
Figure 1 shows chemical structures of MnTCP, MnTPPS (prior art) and (MnTPPS3)2.
Figure 2 shows NMRD of, in ascending order along the left-hand side of the plots, (MnTPPS3)2, MnTCP, MnTPPS (prior art), and Gd-DTPA (prior art). T1 relaxivity values were measured per Mn(III) or Gd(III) up to 1 T.
Figure 3 shows Ti weighted spin echo phantom images (TR = 122 ms, TE =
18.5 ms ) of Gd-DTPA, MnTCP, MnTPPS and (MnTPPS3)2 at 3 T and 25 C. (A) A
schematic diagram of how the solutions are placed. (B) The corresponding phantom Images produced by the 3 T scanner.
Figure 4 shows Ty-weighted spin-echo MR's at 31. A dose of 0.05mmo1 Mn/kg of MnTCP, MnTPPS, and (MnTPPS3)2 was introduced into rats via tail vein injection.
DETAILED DESCRIPTION
An embodiment of the invention is represented by a porphyrin compound of formula (A), exemplified here by MnTCP:
E R2 c02-\ R1 N N N
F / 10C /7\ CO r N N N N
/
Re R7 co (A) MnTCP

In MnTCP, each of R1 to R8 of a compound of formula (A) is a hydrogen atom, and each of 0, E, F and G is a carboxyl group, shown in the ionized form for convenience, and the metal complexed by the porphyrin ring is manganese, which is Mn(111) in the exemplified embodiment, described below.
Another embodiment of the invention is represented by a porphyrin compound of formula (A-LD) exemplified by (MnTPPS3)2:
-"
-R Ra R
N N Nr=¨=.
F /1,A\
N N
N\

R. \ / 72 / "R2 G R" R14 1122 133 R"
A-LD
S. . =
\ \

N N N"*"=
/\N 404 \ *
N N
SOr 10 (MnTPPS3)2 in (MnTPPS3)2, substituent 0 of compound A is LD in which mc) = 0 and I-D1 is a biphenyl group in which each phenyl group is para-substituted, each of R1 to R8 and R17 to R24 is a hydrogen atom, and each of D3, D4, D5, E, F and G is a para-sulfonated phenyl group, shown in the ionized form for convenience, and the metal complexed by each porphyrin ring is manganese, which is Mn(III) in the exemplified embodiment, described below.
Embodiments of the invention include compounds of formula (A) similar to (MnTPPS3)2 in which aromatic rings of the linkers bear solubilising groups, such as sulfonate groups:
N N.¨ N N"'"' 411 SOr = * \ /A\ 411 N N N\

SO,- so, õ
N N "==== """
/N
-04 itA \ õA\ / SOr N N N

SO,- SOr -.
\ N\ /r4.- \ N / N''''.
'W'N N \
N N

\ / 1 , , so, sch Another polyporphyrin related to (MnTPPS3)2, is one in which substituent 0 of compound A is LD and LD and LD1 are biphenyl groups, m is from 1 to 30, each of R1 to R24 is a hydrogen atom, and each of Dl, D2, D3, D4, D5, E, F and G is a para-sulfonated phenyl group:

-,õ =-. \ -, --- \ -.
a lit \ i >1( / 0 0.
...._.=. " N N

\ ,./. /

so. so. .

An embodiment of the invention is a compound of formula (A) in which substituent D is LD and m = 0 and L 1 is a phenyl group linking porphyrin rings by through covalent bonds at para-positions, each of R1 to R24 is a hydrogen atom, and each of D3, D4, D5, E, F and G is a para-sulfonated phenyl group, shown in the ionized form for convenience, and the metal complexed by each porphyrin ring is manganese, which is Mn(III):
=
N N N N"--\
" / 110 N" N 411 N N

803. $O3 Another embodiment of the invention is a compound of formula (A) in which substituent D is LD and MD :"-= 0 and L01 is a covalent bond, each of R1 to R24 is a hydrogen atom, and each of D3, D4, D5, E, F and G is a para-sulfonated phenyl group, shown in the ionized form for convenience, and the metal complexed by each porphyrin ring is manganese, which is Mn(III):

S.
\ \
\N N
N\ """==
\"
N N
S.

Another embodiment of the invention is (MnTCP)2:
cor co2-N N N
-20C \ )A /Mkµ
Nf\ N
\ 40/ /
co CO2-(NinTCP)2 is thus a compound of formula (A) in which substituent D is LD and m = 0 and LD1 is a covalent bond linking mesa-positions of porphyrin rings, each of R1 to R7 and R17 to R24 is a hydrogen atom, and each of D3, D4, D5, E, F and G is a carboxyl group, shown above in the ionized form for convenience, and the metal complexed by each porphyrin ring is manganese, A related polyporphyrin is one in which substituent D of compound A is LD and L and L 1 are covalent linkages between meso-positions of porphyrin rings, m is from I to 30, each of R1 to R24 is a hydrogen atom, and each of DI, D2, D3, D4, D5, E, F and G is a carboxyl group:
CO2COr \ N \ N N"'"` \ N\ /N
\
= \ 1,4s /14Q\ CO2 N N N N N
\ /

c(x coz co2 Embodiments of the invention include polyporphyrins in which each of D, E, F
and G includes a porphyrin ring. In one such embodiment, D, E, F and G are LD, LE, LF, and LG, respectively in which m , mE, mF and mG are all equal to zero; each of D3, D4, D5, E3, E4, E5, F3, t" -4, F5, G3, G4 and G5 is a para-sulfonated phenyl group; each of 01, E1, L LFI and LG1 is a biphenyl group; and all a-positions of the porphyrin rings are unsubstituted i.e., R1 to R8, R17 to R24, R49 to R58, R81 to R88, and R113 to R12 are all hydrogen atoms:
60, N 44^=-C
OPP
+4 N N N
\\. \
* 40 " \ SO>
N N
N
\ /
I NI

\
N N
"
N

NOI

In another such embodiment, in which each of D, E, F and G includes a porphyrin ring, D, E, F and G are LD', LE', LF' and LG' wherein 171D1, mD2, mE1, mE2, mF1, mF2, m31 and mG2 are all equal to zero; each of 03, D4, D5, DB, D9, Dio, E3, E4, E5, Es, E9, Eio, F3, F4, F5, Fs, F9, F10, G3, G4, G5, u- =-=8, G9 and G18 is a para-sulfonated phenyl group;
and all fl-positions of the porphyrin rings are unsubstituted i.e., R1 to R8, R17 to R24, R33 to R40, R49 to R88, R88 to R72, R81 to R88, R97 to R184, R113 to R129 and R129 to R138 are all hydrogen atoms:
S.' 0 a ar -Ca a a a=A' 4111W 11, 0111.1 's*
a === ". 0 a-One can thus see that disclosed embodiments encompass monomeric, dimeric and oligomeric porphyrins. In preferred embodiments, the molecules are free of gadolinium, and M can be manganese, either Mn(II) or Mn(III), preferably Mn(III). Useful as contrast agents, compounds of the invention include substituent groups that render the compound soluble in water i.e., a biological medium provided by the human body in the context of clinical examinations, particularly, plasma, blood and biological fluids.
Field-dependent-T-1 relaxivities of MnTCP and (MnTPPS3)2 were examined and compared to known agents, IVInTPPS and Gd-DTPA. Chen at al. first reported the relaxivity of MnIPPS at -0.5 1 (20 MHz)17, and Konieg and colleagues subsequently measured the T1 Nuclear Magnetic Resonance Dispersion (NMRD) profile (field-dependent relaxivity) of this monomeric MnP18 and found that it exhibits "anomalous high relaxivity", considering there are only four unpaired electrons (S = 4/2) in Mn(III) relative to seven in Gd(III), The relaxivity of MnTPPS peaks at 0.2 T at 37 C and plateaus at > 10 mhes"1 up to 11.15 The rigidity of the porphyrin scaffold reduces internal rotation and efficiently lowers the rotational diffusion rate of the CM. The electron configuration of the complex is important to determining relaxivity. Since porphyrins have large conjugated TT systems, electronic properties at the paramagnetic center can be tuned by introducing different functional groups on the porphyrin ring. Structural modifications made available by approaches described herein, such as appending polar groups to the porphyrin ring can not only optimize the electronic properties but also be made to tune the CA's pharmaco-kinetics. Small and polar porphyrins can be used as extracellular fluid CAs since they tend to be cleared rapidly by the kidney. Large porphyrins that have relatively high relaxivity and longer retention times in the body can be used for targeted imaging.
Porphyrin chelates can have extended applications such as PET imaging (replacing Mn(III) with a radioactive isotope 51Mn. Moreover, fluorescence imaging and photo-dynamic therapy (PDT) can be performed if diamagnetic versions, such as metal-free or 16 Za(11) ¨inserted porphyrins are used19.
NMRD profiles were obtained to demonstrate continuous field-dependent T1 relaxivities. These were recorded using a field cycling NMR relaxometer covering magnetic fields from 0 to 1 T. As shown in Figure 2, compared to MnTPPS, MnTCP, and Gd-DTPA, the dimeric (MnTPPS3)2 exhibited the highest relaxivity per Mn at fields above ¨ 0.2 T. The relaxivity peak of (MnTPPS3)2 occurs close to 1 T and this broad peak extends to higher fields of 3 T and above, favoring high relaxivity at high magnetic fields. Although MnTCP displayed a lower relaxivity than MnTPPS at clinical field strengths, it was still found to be substantially higher than Gd-DTPA at fields above 0.2 T.
26 Relaxivities of MnPs at 3 T were measured on a clinical MRI scanner (Philips Achieve). Each of the four CAs were prepared in a series of increasing concentrations, 0, 0.05, 0.1, 0.2 and 0.5mM, and imaged using an inversion-recovery spin-echo pulse sequence with varied inversion times T1 and a multi-echo spin-echo sequence with varied echo times TE. As demonstrated in Figure 3, by comparison of samples at the same concentration, (MnTPPS3)2 shows the highest signal intensity on T1 weighted images due to highest T1 relaxivity, and MnTCP exhibits significantly higher relaxivity than Gd-DTPA at 3 T. The ri values, listed in Table 1, also confirmed the high efficacy of MnPs at high field and increased high-field T. relaxivity per Mn with increased porphyrin size. The r1 values in Table 1 were derived by calculating Ti relaxation times from the inversion-recovery images and then linearly fitting the Ti relaxation rates to obtain the relaxivity ri. T2 relaxivities of the MnPs were also calculated and are listed in Table 1. The relatively weak T2 effect (negative contrast enhancement) does not significantly compromise positive contrast enhancement. Overall, in vitro characterizations suggest that all MnPs are efficient Ti agents and useful for high field applications.
Table 1: Ti and T2 relaxivities for the Mn-Porphyrins Porphyrin r1 (m1V1-1 s') r2 (mlµe s"1) MnTCP 7.90 9.11 MnTPPS 8.63 10.4 (MnTPPS3).2 14.1 18.0 MnPs MnTCP and (MnTPPS3)2 were administrated in rats and submitted for MR1 studies on a 31 clinical scanner (Philips Achieve), with MnIPPS as a reference, and found to be efficient Ti CAs for in vivo applications, MnTCP and (MnIPPS3)2. A

relatively low dose, 0.05 mmol Mn/kg (typical dose for clinical Gd-based As is ¨ 0.1 .. mmol Gd/kg) was chosen based on the in vitro relaxivity values described above. All MnPs were found to exhibit significant Ti contrast enhancements in vivo after intravenous injection, allowing the pharmacokinetic properties of MnPs, including tissue distribution, metabolic pathway and clearance rate to be analyzed from the in vivo MRI
data.
As shown in the whole body images of the rats, Figure 4, the small and polar MnTCP rapidly accumulated in the kidney within 10 minutes post injection and the majority of kidney enhancement was quickly relocated into the bladder within an hour.
The desired rapid clearance of MnTCP via renal filtration was further confirmed by urine sample analysis. The characteristic reddish color of MnPs was clearly visible by eye in the urine samples. The concentrations of MnPs can be accurately quantified by both UV-vis and Mn atomic absorption (Mn AA) spectroscopic analyses. Very high concen-trations of Mn? were detected in urine 60 minutes (11.7 1,1M) after injection.
Absence of MnTCP in urine sample collected about 24 h post injection suggested complete clearance, similar to Gd-DTPA. In contrast, although MnTPPS showed similar kidney Ti enhancement 10 minutes post injection, the signal lasted significantly longer than MnTCP and was still visible in the image 1 day post-injection. In the same image, the clear liver enhancement suggested a dual-metabolic pathway through both kidneys and liver for MnTPPS, as reported in the literature25. The significantly slower renal clearance process of MnTPPS vs MnTCP was confirmed by urine sample analysis. The concen-tration of MnTPPS 60 min post injection, was 4.41 j.tM in the urine sample, lower than that of MnTCP. Moreover, a significant amount of MnTPPS (1.12 uM) could still be detected in urine 24 hours post-injection. For the dimeric porphyrin, (MnTPPS3)2, no bladder enhancement was detected over the three days of the experimental period.
Although accumulation was observed in the kidney, the dimer did not cross the glomerulus and did not collect in urine on the tubular side. The exclusion of the renal metabolic pathway for (MnTPPS3)2 was further confirmed by urine sample analysis. No MnP signal was found by either Mn-AA or UV-vis in urine over the 72 hour post-injection period. The significant liver enhancement suggests that (MnTPPS3)2 was mainly metabolized by the liver. Noticeably, (MnTPPS3)2 exhibited relatively long-lasting enhancement in the blood vessels and in the heart. Overall, these observations demonstrated the feasibility of (MnTPPS3)2 as a blood-pool CA as well as a tissue-selective agent for liver imaging.
As Ti agents, polyporphyrins (two or more covalently linked porphyrin rings) have multiple paramagnetic centers per molecule, and have slower rotational reorientation rates (TR) to increase the T1 relaxivity, particularly at high magnetic fields according to the SBM theory. For in vivo applications, relatively low doses are needed, reducing toxic exposure of a subject. The size and geometry of a polyporphyrin can be tailored to adjust the pharmacokinetic properties, including diffusion rate, tissue specificity and metabolic pathway to match the different criteria for different applications, such as tissue-specific targeted imaging or dynamic contrast-enhanced (DCE) MRI.

Monomeric water soluble porphyrins can be rapidly cleared through renal filtration after in vivo administration, reducing the exposure time and thus toxicity risk.
Monomeric orphyrins can be structurally modified to positively influence the effect of electron configuration on relaxivity. The optimized monomers can then be used directly for in vivo applications or as described herein as building blocks or precursors to dimeric and oligomeric porphyrins.
As indicated above, porphyrin compounds described herein are encompassed by the family of compounds represented by formula (A):

N\
F /M\
N
R6 0 (A) Ring substituents D, E, F and G are covalently bonded to the mesa-positions of the porphyrin ring. The R-groups are covalently bound to the 3- and 4-positions of pyrrole groups of the porphyrin ring.
The compounds are water soluble, so contain at least one water-solubilizing group. Water-solublizing groups of the invention render a compound suitably soluble in an aqueous medium for use as a CA agent.
Examples of water-solubilizing groups include the anionic groups carboxyl, sulfonate, phosphate (-0P03H2), alkylphosphate (-0P03RH), phosphonate (-P03H2), alkylphosphonate (-P03R11), phosphinate (-P02H) and alkylphosphinate (-P02R).
The alkyl group of the of an alkylphosphate or alkylphosphonate is typically a straight chain or branched C1-C10 alkyl group, e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl.

Examples of water-solubilizing groups include the cationic groups amino, alkylamino, dialkylamino, alkylammonium (-NR3+), aminoalkyl, guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), amido (-C(0)NH2, heterocyclic cations. A heterocylic cation is a cycloalkyl or aryl group containing a nitrogen atom in its ring, e.g. alkyl pyridiums such as methyl pyridiniums:
CH
¨

b+ + , A porphyrin compound such as the MnTCP of the examples can include multiple water-solubilizing groups. Such groups can be anionic, such as the carboxyl group of MnTCP, cationic, or can be a mixture of both, so that the compound can be viewed as zwitterionic. A carbon-based substituent e.g. alkyl containing a water-solubilizing group such as a carboxyl can also contain an amino group and thus also be zwifterionic.
A water-solubizing group can also be a neutral hydrophilic group, which can be instead of, or in addition to one or more ionic water-solubilizing groups.
Such groups include polyols, polyethylene oxides (PEG), diethylene glycol (-0CH2CH2OCH2CH2OH) carbohydrates e.g., glucose, polysaccharides, dextrins, cylclodextrins, amino sugar, glucosamine, giucamine, their deravatives, and the following groups:

where n = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
Water-solubilizing groups that are referred to as ionic are groups are charged at physiological pH. By "physiological pH" or "physiological conditions" is meant water at a pH of about 7.5 and about 37 C, and an ioinic strength of about 150 mM. Basic groups, such as amino groups that are converted to positively charged groups under physio-logical conditions, and acidic groups, such as carboxyl groups that exist as negatively charged groups under physiological conditions are water-solubilizing groups.
Under such conditions, at least 10%, but more preferably at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 96%, or at least 96%, or at least 97%, or at least 98%, or at least 99%
of the water-solubilizing group exists in its charged Le. ionic form under physiological conditions. Such positively charged groups bearing a proton such as a protonated amino group (ammonium), have a pKa under such conditions that is less than about 8.5.
More preferably, the pKa is less than 8, or less than 7.5, and more preferably less than 7,0, more preferably still less than 6.5. Likewise, negatively charged groups that are unprotonated under physiological conditions, such as a carboxyl group (carboxylate in unprotonated form), have a plc, under such conditions that is less than about 8.5. More preferably, the pKa is less than 8, or less than 7.5, and more preferably less than 7.0, more preferably still less than 6.6.
It is also to be understood that terms such as carboxyl encompass such groups whether or not in ionized form as part of the compound, so cover salts Stich as sodium carboxyiate (-0O2"Na+), etc.
As describe elsewhere, in embodiments, carbon atoms of a polyporphyrin ring or rings of a compound can bear one or more substituents have one or more hydrogens replaced by e.g., an alkyl, aryl group, etc. When such a substituent of a polyporphyrin bears a water solubllising group such as an ionic or hydrophilic group e.g., carboxyl or sulfonate, then the substituent is itself a water solubilising group.
Of course, a monoporphyrin compound can also include one or more substituents such as alkyl groups covalently linked to carbon atoms of the porphyrin ring, and these substituents can bear ionic or hydrophilic water-solubilizing groups, For use as an MRI agent, a compound is typically soluble in amount of between 10 pM to at least 1 M. Other minimum solubility ranges include from 0.0001 M
to 1 M, 0,001 M, 0.01 M to 1 M, 0.1 M to 1 M, or the minimum solubility could be at least 0.0001 M, 0.001 M,0.01 M or 0.1.
The metal "M" is a paramagnetic metal ion, and includes Mn(II), Mn(III), Fe(II), Fe(III), Gd(III), Cu(I), Cu(II), Ni(II), Ni(I) and Ni(III). Advantageously, the ion can be Mn(II) and Mn(111), also referred to as Mn2+ and Mn3+, respectively, due to its relatively low toxicity. Mn(111) is preferred among the two oxidation states, due to the higher stability. It is possible for there to be more than one type of metal ion, paramagnetic or diamagnetic to be incorporated as part of a compound. At least one porphyrin ring of a polyporphyrin compound of the invention is metalated with paramagnetic ion, but it is thought preferable that all porphyrin rings of a polyporphyrin compound be metalated for use as an MR1 contrast agent.
Porphyrin substituents appended by covalent linkages to the porphyrin rings, when specifically defined, are designated as R-groups, R1, R2, etc., and the letters D, E, F, G, D1, D2, etc. When so-defined, such substituents are monovalent radicals, and it is understood by the skilled person that such groups may be denoted for example as "R"
or "-R". So a fluorine radical, for example, may be designated as "F" or "-F"
without confusion.
An "alkyl" group indicates the radical obtained when one hydrogen atom is removed from a hydrocarbon. An alkyl group has 1 to 20, 1 to 12, such as 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 or 2 carbon atoms, or 1 carbon atom. The term includes the subclasses normal alkyl (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyi, isopentyl, hexyl and isohexyl.
A "cycloalkyl" group indicates a saturated cycloalkane radical having 3 to 20 .. carbon atoms, so can have 3 to 10 carbon atoms, in particular 3 to 8 carbon atoms, such as 3 to 6 carbon atoms, or 6 carbon atoms and includes fused monocyclic, bicyclic, polycyclic, fused, bridged, or Spiro polycyclic ring structures, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
A "heterocydoalkyl" denotes a cycloalkane radical as described above in which one or more CH2 groups atoms e.g., 1, 2, 3 or 4 CH2 groups are replaced by corres-ponding heteroatoms, 0 or S, or in which one or more CH groups are replaced by a corresponding heteroatom N, an example of which is piperazinyl.
An "alkenyl" group indicates an alkyl group in which 1, 2, 3, 4 or 5 unsaturations (double bonds) replace a corresponding number of -CHCH- groups, examples being ethenyl, propenyl, butenyl, pentenyl or hexenyl.

A "cycloalkenyl" group indicates mono-, di- tri- or tetraunsaturated non-aromatic cyclic hydrocarbon radicals such as containing 3 to 20 carbon atoms, including fused monocyclic, bicyclic, polycyclic, fused, bridged, or spiro polycyclic ring structures, and include groups containing 3 to 10 carbon atoms, such as 3, 4, 5 or 6 carbon atoms, e.g.
cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cylcoheptenyl.
A "heterocycloalkenyl" indicates a cycloalkene radical (cycloalkenyl group) in which one or more CH2 groups atoms e.g., 1, 2, 3 or 4 CH2 groups are replaced by corresponding heteroatoms, 0 or S, or in which one or more CH groups are replaced by a corresponding heteroatom N, examples being dihydrofuranyl and 2,5-dihydro-1H-pyrrolyl.
An "aryl" group is a radical of aromatic carbocyclic rings having 6 to 20 carbon atoms, such as 6 to 14 carbon atoms, or 6 to 10 carbon atoms, particularly 5-or 6-membered rings, that can be fused carbocyclic rings with at least one aromatic ring, such as phenyl, naphthyl, indenyl and indanyl.
A "heteroaryl" group is a radical containing at least one aromatic ring having 1 to 6 0, S and or N heteroatoms, and 1 to 20 carbon atoms, such as 1 to 5 heteroatoms and 1 to 10 carbon atoms, or 1 to 5 heteroatoms and 1 to 6 carbon atoms, in particular 5- or 6-membered rings with 1 to 4 heteroatoms, and can include fused bicyclic rings with 1 to 4 heteroatoms, and wherein at least one ring is aromatic, such as pyridyl, triazolyl, ouinolyl, isoquinolyl, indolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolyl, benzimidazolyi and benzofuranyl.
"Arylalkyl" denotes an aryl radical covalently joined to an alkyl group such as a benzyl group.
A "heteroarylalkyl" group indicates a heteroaryl radical covalently joined to an alkyl group.
An "alkynyl" group is a hydrocarbon radical having 1 to 5 triple C--C
bonds -CC-) and 2 to 20 carbon atoms, typically having 2 to 10 carbon atoms, or 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, examples being ethynyl, propynyl, butynyi, pentynyl or hexynyl.

"Heteroalkyl, heteroalkenyl, heteroalkynyl" refer to alkyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatoms 0, S or N.
6 "Halogen" indicates a substituent from the seventh main group of the periodic table: fluoro, chloro, bromo and ioclo.
The term "haloalkyl" indicates an alkyl group substituted with one or more halogen atoms as defined above, e.g. difluoromethyl. An alkyl optionally substituted with halogen is a haloalkyl when so substituted.
In general, an optional substitution with specified groups, radicals or moieties means that the subsequently described substitution may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. An atom with unsatisfied valence(s) is assumed to have the hydrogen atom(s) to satisfy the valences.
*Phosphate" refers to a radical -0P(0)(OR)(OR") where R` and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl.
"Sulfonate" refers to a radical -S(0)(0)OR', where R' is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl.
"Carboxy" or "carboxyl" means the radical -C(0)0H.
The term "hydroxyalkyr denotes an alkyl group substituted with one or more hydroxyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl.
An "alkoxy" group indicates a radical of the formula -OR' in which R' is alkyl such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, etc.
The term "alkoxycarbonyl" indicates a radical of the formula -C(0)-0-R' in which R' is alkyl, such as methoxycarbonyl, ethoxycarbonyi, n-propoxycarbonyl, isopropoxy-carbonyl, etc.
The term "alkylcarbonyr indicates a radical of the formula -C(0)-R' in which R' is alkyl, such as acetyl.

A "heterocyclic ring" includes heteroaryl, heterocycloalkyl and heterocylcoalkenyl and further includes annelated ring systems with each other or with cyclic hydrocarbons.
The term "pharmaceutically acceptable salt" indicates salts formed by reacting a compound of formula (A) with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, 2,2-dichloroaetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D-glucuronic, methanesulfonic, salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane-1,2-disulfonic, 2-hydroxy ethanesulfonic acid, toluenesulfonic, sulfamic or fumaric acid. Pharmaceutically acceptable salts of compounds of formula (A) may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, ammonia or the like, or suitable non-toxic amines, such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example hydroxyethylamine, bis-(2-hydroxyethyl)-amine, glucamine, N-Methylglucamine cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example NN-dibenzylethylenediamine, and dibenzylamine, or L-arginine or L-lysine. Salts obtained by reaction with a suitable base include, but are not limited to sodium salts, choline salts, 2-(dimethylamino)-ethanol salts, 4-(2-hydroxyethyl)-morpholin salts, L-lysine salts, N-(2-hydroxyethyl)-pyrrolidine salts, ethanolamine salts, potassium salts, tetrabutyl-ammonium salts, benzyltrimethylammonium salts, cetyltrimethylammonium salts, tetramethylammonium salts, tetrapropylammonium salts, tris(hydroxymethyl)amino-methane salts, N-methyl-D-glucamine salts, silver salts, benzethonium salts, and triethanolamine salts.
According to various embodiments, a covalent linkage within a compound of formula (A) is provided by, for example, Lip, where LD may be a covalent bond or a bivalent radical that provides the linkage. So here L is a "linker" that links two groups directly covalently as through a bond, or indirectly via a chemical moiety i.e., bivalent radical. Such a bivalent radical corresponds to a monovalent radical obtained when a hydrogen atom is removed therefrom. Where, for example, an aryl or cycloalkyl group provides such linkage and is therefore bivalent, the bivalent aryl or cycloalkyl is referred to as "arylene" or "cycloalkylene", respectively. Examples of these respective groups are thus -C6H4- and -C6H10-, based on the phenyl and cyclohexyl groups. The terms "alkylene", "alkenylene", "heterocycloalkylene", "cycloalkenyiene", "heterocyclo-alkenylene", "heteroarylene", "arylalkylene", "heteroarylalkylene", "alkynylene", "haloalkylene" etc. are similarly derived terms. Other bivalent linkers are -X-C(Y)- in which X and Y are independently selected from the group 0, S and NH, and -XC(Y)-2,- in which X, Y and Z are independently selected from the group 0, S and NH.
According to various embodiments, a covalent linkage within a compound of formula (A) by L where the linker covalently links three groups, as in the moiety (ED'), so the linker is a trivalent radical. Such a trivalent radical corresponds to a bivalent radical obtained when a hydrogen atom is removed therefrom, examples of which are:
and These linkers are referred to herein as "trivalent cyclohexyl" and "trivalent phenyl"
groups, respectively, and other trivalent linkers are correspondingly termed.
Linkers, such as those illustrated above, can also bear water-solubilizing groups.
It will thus be appreciated that a variety of water soluble porphyrin compounds useful as MR1 contrast agents are made available through this disclosure. In addition to monomeric porphyrins described herein, there are a number of polyporphyrins in which porphyrin rings are covalently linked to each other. As described in greater detail elsewhere herein, one general example is a diporphyrin in which porphyrin rings are directly covalently linked to each other through the meso-positions of the peripheral twenty carbon ring:

N 14¨""" N
\ \
Here, for the sake of simplicity, substituents of porphyring rings are omitted, be they hydrogen atoms, water-solubilizing groups, etc. Porphyrin ring-subsitutents can be the same or different from ring to ring of a compound, as can be the paramagnetic metal, M.
Covalent linkage of porphyrin rings can also be provided by a covalent linker:
N N-- N\
./K \ X
N N N
\
Bivalent covalent linkers, illustrated above as the boxed 'V, are described in greater detail elsewhere herein, Again, as for other polyporphyrins described herein, it is possible that porphyrin subsitutents be the same or different from ring to ring of a compound, as can be the paramagnetic metal, M.
Particular bivalent linkers include:
-CL, ¨d s or NIO S NEI) The linkers provide a rigid link between the porphyrin rings Le., have relatively high conformational rigidity and examples are aromatic ring(s), conjugated or partially conjugated (hyperconjugated) n-bond(s), or rigid systems with saturated bonds, to reduce internal motion.
A rigid linker covalently connects sites in the porphyrin rings, such as carbon atoms in meso-positions of neighboring porphyrin rings, so as to confine movement of those sites with respect to each other within the molecule. So, in aqueous solution at room temperature (21 C) two porphyrin rings directly connected to each other by a covalent bond between meso-carbons can rotate to some extent with respect to the axis defined by that bond, but the distance between those meso-carbons themselves remains essentially unchanged. The degree to which such distance can vary is possible to determine by molecular modeling methods, such as molecular mechanics calculation.
Two such covalently linked porphyrin rings, be it through a bond or linker such as para-carbons of phenyl ring (-C6114-), etc., are rigidly linked if the distance between the linking sites does not vary significantly due to conformational changes.
Polyporphyrins can have more than two porphyrin rings c,ovalently linked:
N N-""" N N-- N
rs \ A / A / \
N N N N n N\
\ I \ \
Here, the linker can instead be a covalent bond, and such linkages can be different between rings so that a compound includes different linkers between porphyrin rings, and/or covalent bonds acting as linkages. The number "n" in the foregoing is a whole number used to designate the number of porphyrin rings between the end rings.
Various values of n, i.e., 0, 1, 2, 3 ... etc. are described in greater detail elsewhere herein.
Other arrangements of porphyrin rings are possible, such as:

/1\
N N
,00#
N\ /N NN N
\Aim\ \
N N
\

N
\ .0/
In such configuration, one, two, three or all of the four external porphyrins can have additional porphyrin rings covalently appended thereto as described immediately above. It is also possible that any one of the above-illustrated porphyrin rings be omitted to obtain a configuration in which three porphyrin rings are coviently linked to three meso-positions of a single porphyrin ring, again such linkages being provided by any combination or bivalent linkers or direct covalent bonds. Two of the illustrated porphyrin rings in neighboring positions can be omitted such that a porphyrin ring is linked to a pair of porphyrins through neighboring or vicinal meso-positions of its peripheral carbon ring. Additional porphyrin rings can be appended to one or more meso-positions of the illustrated porphyrins. In the foregoing example of a polyporphyrin, the porphyring ring bound to four porphyrins does not necessarily bear a water-solubilizing group.

Additionally, neighboring porphyrin rings in a compound can be linked by a trivalent linker:
N\ \/M\/

N
tkr \ 1 N. N
Again, one, two or all three of the illustrated porphyrin rings can further have additional porphyrin ring(s) covalently appended thereto as described for the above-illustrated configurations.
The foregoing examples illustrate polyporphyrin compounds in which all the porphyrin rings are shown as being metalated i.e., containing a paramagnetic metal ion "M". It is possible for one to all of the porphyrin rings to be metalated.
Bivalent and trivalent linkers themselves can bear one or more water-solubilizing groups as well as other substituents.
Compounds of the invention are particularly useful as CAs at relatively high magnetic fields, for example at 1 -I or higher, 1.5 T or higher, 3 T or higher, 4.31 or higher, 7 T or higher, 9.4 T or higher, 11.7 T or higher, and up to 21 T.
As described above, particular compounds exhibit ri above 4 mrvtl s' at IT or higher fields.
The present invention provides CAs that can be used to generate an image of a human or non-human subject involving administering the contrast agent to the subject e.g., vascularly, via the gastrointestinal tract, etc. and generating an image of at least a part of the subject to which the contrast agent has been distributed.
Known methods for administering diagnostics can be used to administer CAs.
For example, fluids that include pharmaceutically and physiologically acceptable fluids, including water, physiological saline, balanced salt solutions, buffers, aqueous dextrose, glycerol or the like as a vehicle, can be administered by any method used by those skilled in the art. These solutions are typically sterile and generally free of undesirable matter. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH
adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of active agent in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration and imaging modality selected. The invention 16 further provides formulations comprising CA and a pharmaceutically acceptable excipient, wherein the CA is formed according to any of the embodiments described herein, and wherein the formulation is suitable for administration as an imaging enhancing agent and the CA is present in an amount sufficient to enhance an MRI
image. These agents can be administered by any means in any appropriate formulation.
Detergents can also be used to stabilize the composition or the increase or decrease the absorption of the composition. Other physiologically acceptable compounds include Wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. One skilled in the art would appreciate that the choice of acceptable carrier, including a physiologically a acceptable compound depends, e.g. on the route of administration and on the particular physio-chemical characteristics of any co-administered agent.
Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, rectal, vaginal, and oral routes. A
CA composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings e.g., oral mucosa, vaginal, rectal and intestinal mucosa, etc., and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, a CA composition may be introduced into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. A CA composition can be delivered by any means known in the art systematically e.g., intra-venously, regionally or locally e.g. intra-or pad-tumoral or intra-cystic injection, e.g. to image bladder cancer by e.g., intra-arterial, intra-tumoral, intra-venous, parenteral, intra-pneural cavity, etc. For example, intra-arterial injections can be used to have a regional effect e.g. to focus on a specific organ (e.g.
brain, liver, spleen, lungs), For example intra-hepatic artery injection or intra-carotid artery injection may be used. If it is decided to deliver the preparation to the brain, it can be injected into a carotid artery or an artery of the carotid system of arteries e.g., ocipital artery, auricular artery, temporal artery, cerebral artery, maxillary artery, etc. The present invention includes pharmaceutical compositions which include a CA alone or with a pharmaceutically acceptable carrier.
An embodiment of the invention is a method of detecting a condition in which cells express a characteristic surface protein. The method includes administering to the cells a CA comprising a compound of the invention that is coupled to an agent which binds to the protein, and obtaining an MRI image of the cells. The condition can be a lung disease, emphysema, asthma, a cancer, particularly breast, prostate, or brain cancer, ischemia, particularly stroke, cardiac infarct, muscle ischemia, chronic kidney disease, or liver disease, particularly cirrhosis or cancer of the liver.
Administering the CA to cells can be in vivo or in vitro.
The invention is also a method for monitoring transport of an effector agent to a target found within a cell. This aspect includes contacting the cell with a delivery vehicle encapsulating the agent and a CA described herein, and obtaining an Mill image of the cell. The delivery vehicle can be a nanoparticle, a nanocapsule or a liposome.
The invention is also a method of labeling a cell. The method includes administering to the cell a CA comprising a compound of the invention coupled to an agent which binds to cell. The method can further include detecting the labeled cell by obtaining an MRI image thereof. The agent can be an antibody.
The invention includes amethod of screening for therapeutic agents useful in the treatment of a disease. This can include contacting a molecule comprising a test compound coupled to a CA disclosed herein and contacting the molecule with a target cell, and detecting the labeled cell by obtaining an MRI image thereof.
A CA and agent that includes coating material may be made up of, for example, nanoparticles or nanocapsules, liposomes and the like. A suitable means is the encap-sulation in biodegradable polymers with controllable release, such as polylactide and/or polyglyoolide. In this context, the coating material may be chosen such that the agent is released in a predetermined manner. Such coating materials have been described in the literature and the skilled worker can select, from a multiplicity of materials, the material best suited to the purpose in hand.
The agent and CA are encapsulated with the encapsulation material, or coated therewith, in a known manner. Encapsulation means that the agent is shielded by the polymer from the physiological environment, such that it is not altered or degraded until It arrives at the target. The encapsulation may be only one layer which surrounds the CA and agent, but it may also be a liposome or nanoparticle or microparticle in which the agent is embedded or enclosed. It may also be enclosed by complexing. A CA
and agent may be covalently coupled to each other prior to encapsulation. A person skilled in the art is familiar with various forms of encapsulation or coating of agents, which can be employed as long as they do not interfere with the binding of e.g., the target-finding agent to its receptor and the introduction of the agent into the cell, and release the agent in the cell. The encapsulation of the agent with the encapsulation material, and/or the preparation of suitable particles, can be done using customary methods. In the simplest embodiment, the active agent is mixed with the encapsulation material, for example a cationic polymer, such as polyethyleneimine, if appropriate in dissolved form.
Liposomes may comprise a lipid such as phosphatidylcholines (lecithins) (PC), phosphatidylethanolamines (PE), lysolecithins, lysophosphatidylethanolamines, phosphatidylserines (PS), phosphatidylglycerols (PG), phosphatidylinositol (PI), sphingomyelins, cardiolipin, phosphatidic acids (PA), fatty acids, gangliosicles, glucolipids, glycolipids, mono-, di or triglycerides, ceramides, cerebrosides and combinations thereof; a cationic lipid (or other cationic amphiphile) such as 1,2-dioleyloxy-3-(trimethylamino)propane (DOTAP); N-cholesteryloxycarbary1-3,7,12-triaza-pentadecane-1,15-diamine (CTAP); N41-(2,3,-ditetradecyloxy)propyll-N,N-dimethyl-N-hydroxyethylamm- onium bromide (DMRIE); N41-(2,3,-dioleyloxy)propyll-N,N-dimethyl-N-hydroxy ethylammonium bromide (DOME); N41-(2,3-dioleyloxy)propyll-N,N,N-trimethylammonium chloride (DOTMA); 3 beta [N-(N',Nt-dimethylaminoethane) carbamolylcholesterol (DC-Choi); and dimethyldioctadecylammonium (DDAB);
dioleoylphosphatidyl ethanolamine (DOPE), cholesterol-containing DOPC; and combinations thereof; and/or a hydrophilic polymer such as polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyl-oxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethyl-acrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxylmethyl-cellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide and combinations thereof.
EXAMPLES
In general, monomeric porphyrins can be synthesized based on the Lindsey method2 from pyrrole and the corresponding aldehydes. Monomers can then be used directly, or after necessary functional group transformations, to build dimeric, oilgomeric or polymeric porphyrins using coupling reactions. After installation of water solubilizing groups, paramagnetic ions e.g., manganese ions are inserted into the porphyrin cores to generate the final products. The sequence of these reaction steps can be varied in certain cases. Examples for reaction steps are described below.
Synthesis of Porphyrin Building Blocks Using different compositions of aldehydes and pyrrole, different porphyrin monomers can be obtained by a Lindsey reaction20, as exemplified in Scheme 1.
Both symmetric (Ri = R2 = R3 = R4) or non-symmetric (at least two R groups are different) porphyrins can be obtained.

\

N a) Lindsey rxn \ NHN"--RAH + '17 R\ / R3 N HN

Scheme 1: General method for synthesis of symmetric or non-symmetric porphyrin monomers.
For certain porphyrin building blocks, protection or functional group trans-formation is necessary before they can be coupled together. Two examples are shown in Scheme 2, including protection of the porphyrin core by zinc insertion and bromination on the porphyrin mesa-position.
=

\ NH N¨ N
b) ZnpAct2 r CAW
\ I \
1 Zn-f = 110 110 \ \
\ NH N¨ MS \ NH N¨ b)Zn(00µ0)2 N \
\ H _________________ Br * /26\ ;
N HN N HN DMF N N
\ 1 /
\
\

2 3 2n-3 Scheme 2: Zinc insertion and bromination of porphyrins.
Coupling of Porphyrins In principle, coupling chemistry can be applied to porphyrin building blocks with complimentary functional groups. Scheme 3 shows examples of three different coupling reactions, including oxidative coupling reaction with hypervalent iodine, Suzuki coupling, and Pd(II)-catalyzed homolytic coupling that could be applied for linking porphyrin rings.

(A) Ra 82 R2 83 R R 83 82 \ R, R, Rs% -=== 83 N Pre \ N /N a) PWA =¨ \
\ 2 \ / \ / 812 / RI fts \ / R3R3 / 14,, R. R. Rs, RN Re Re R. R. Rs

4 8 (B) 82 8, R, Re 82 82 83 83 R R Rf 82 Rs ss tee, \ R, Re / Rf Rs / \ el er¨ N = * elõ, e \ p4" R12 b) Suzuki Coupling R
\ N b Br / 0 12 \ ;10/s, \ RA I

N N N N t4/ Nel RI, \ / 87 8, \ t / 8,, RI, \ eNs j / 8, 83 \ / RI
RR Rs Re R* Re Rio 8,0 - R.R Ro Rio 6 4-Br 7 (C) 83 R. Re 8, 8, 8, R, R. 82 RI Rs Rõ R, \ /N c) IBA F N N N \
8.N/1% / = tE(0 X 2 _____ RI2 \ io A , N N N N
\ 143 8,, \ I / Ri 87 RI, Re Re Rs, Re Rs Ro Rio Scheme 3: coupling reactions for the synthesis of porphyrin aligomers.
a)PhI(OCO-CF3)2 (PIFA), b) Suzuki coupling: 2:1 Tol:DMF, Cs2CO3, Pd(PPh3)4, c) Tetra-n-butylammonium fluoride (TBAF), Pd(PPh3)2Cl2, THF:H20 4:12 air, RT
Installation of Water Solubillzing Groups and Mn-Insertion The final MnPs should be water-soluble for in vivo applications. The polar and water-solubilizing groups, such as sulfonates or carboxylates can be introduced by different methods. By sulfonation reaction with concentrated sulfuric acid, the sulfonates can be installed on the phenyl groups attached to the porphyrin mesa-position;
the carboxylate groups can be generated from the hydrolysis of ester groups pre-installed on the porphyrins. Mn can be inserted into the porphyrins, either before or after the introduction of water-solubilizing groups, as exemplified in Scheme 4.

503- 803' NH N - N H
IIEM N HN aI "12S 4 N N Link \ 11 803 N HN NH N N HN NH N
N , sr03- 903-N N õN
b) Mn(0A02 -03S =, Mn. , Mn$03-N N

Mn-10 0 = R 0 OR 0 a RO NH N ________ 0 b) Mna2 RO N õ-N C) HydrOlysis '0 0 iriln RO 0 RO 0 '0 0 11 Mn-11 12: MnTCP
Scheme 4 Examples of introducing sulfonates or carboxylates, and the insertion of Mn in porphyrins. a) Sulfonation: conc. H2S0480 C, 9h; b) Mn insertion:
lvin(0Ac)2 or MnC12, DMF, reflux c) 2 M NaOH, THF, Et0H, reflux, 12 h

5 Synthetic Procedures All reagents and solvents were of commercial reagent grade and were used without further purification except where noted. 1H NMR spectra were performed at 500 MHz. Mass spectra were obtained on electron-spray ionization mode. UV-vis spectra were recorded on an Agilent 8453 UV-Visible Spectroscopy Systems. Column 10 Chromatography was carried out using Caledon Silica Gel 60; 50-200 microns 70-300 mesh, or using Sephadex TM LH-20 with dry bead size of 18-111 pm from GE
Health Care Dialysis was performed with Sigma Aldrich Pur-A-LyzerTM Mega 3500/1000 MWCO. Reverse Phase column was loaded with Agela Technologies C18 Flash 40-60 pm. Cation ion exchange was performed using an Amberlite IR120, H resin, (a) Synthesis of porphyrin 121 2.31 g (9.9 mmol) of 4-boronopinacolbenzaldehyde was added to a RB flask. 3.0 ml (30 mmol) of benzaldehyde was then added followed by 400 ml of anhydrous dichloromethane. The flask was sealed and N2 was bubbled through for 20 min.
2.79 ml (40.2 mmol) of freshly distilled pyrrole was added together with 0.63 ml of BF3.0Et2 (12.4 mM). After 1 h of reflux in the dark, 7.94 g (35 mmol) of DDQ was added and the reaction was allowed to reflux for another 1 h. The solution was filtered with basic alumina and column chromatography with 6:4 dichloromethane-hexane solvent system was run through silica to remove TPP. The solvent was switched to 8:2 dichloro-methane-hexane to elute the product. The product (30mg) was isolated with 4%
yield, characterized by NMR and MS. 1H NMR (500 MHz, CDCI3): 6 8.84 (8H, s, por-11), 8.18-8.25 (10H, m, Ph), 7.72-7.78 (9H, m, Ph), 1.50 (12H, s, alkyl), -2.78 (2H, s, NH). ES!
MS found m/z = 741.3 ([M+Hr), calcd for C30H42BN.402+, m/z = 741.3.
(b) Synthesis of porphyrin (TPP)222.
73.6 mg (1 eqv) of 1, 9.0 mg of Pd(PPh3)2Cl2(0.1 eqv), 35 mg of tetrabutylammonium fluoride (leqv), were added to a pear shaped flask. 10 ml of 2:8 water and THF
solvent mixture was added and allowed to stir at room temperature and opened to oxygen. After 5.5 h, the reaction was stopped and dried by rotavap. The product is barely soluble in chloroform and diethyl ether, thus hexane:chloroform 7:3 and diethyl ether were used to rinse off porphyrin impurities. Filtration was performed and the purple crystals residue were rinsed with cold CHCI3. 48.5 mg of product was obtained (80 %). 1H NMR
(500 MHz, CDCI3): 6 9.06 (4H, d, J = 4.7 Hz, por-11), 8.94 (4H, d, J = 4.7 hz, por-11), 8.88 (8H, s, por-(1), 8.47 (4H, d, J = 8.1 Hz, Ph), 8. 35 (4H, d, J = 8.1 Hz, Ph), 8.30-8.21 (6H, m, Ph), 7.84-7.72 (9H, m, Ph), -2.71 (2H, s, NH). ES! MS found m/z= 1227.5 ([M+Hr), calcd for C881158N8 , rig& = 1227.5 (c) Sulfonation of porphyrin (TPP)2 to produce (TPPS3)2, modified from the literature method23.
30 mg of (TPP)2 was allowed to react in 2 ml of conc. Sulfuric acid at 80 C
for 9 h. The solution turned from red to green upon acidifying. After the reaction, the porphyrin solution was poured into a beaker of ice, diluted and neutralized with 1 M
NaOH until the solution turned deep red. The solution was concentrated and the porphyrin solution was rinsed off from Na2SO4 salt with cold water. The porphyrin solution was dialyzed using a 3500 MWCO membrane to remove the excess salt. 40 mg of product was obtained (96 %).111 NMR (500 MHz, DMSO-d5): 59.06 (4H, d, J = 4.6 Hz, por-I1), 8.98 411, d, J = 4.6 Hz, por-11), 8.87 (8H, s, 8.49 (811, m, Ph), 8.25-8.15 (12H, m, Ph), 8.12-8.00(12H, m, Ph), -2.86 (4H, s, NH). ESI MS found mlz= 283.4 ((Mr), calcd for C88H48N8018S66" , rn/z = 283.4.
(d) Mn insertion into porphyrin (TPPS3)2 to produce (MnIPPS3)2.
10.7 mg (5 eqv) of Mn(OAc)2 and 10 mg (1 eqv) of (TPPS3)2 was used for Mn insertion.
The reaction occurred for overnight at 115 C with stirring in 3 ml of DMF.
DMF was removed by distillation. The crude product was dried and dissolved in pure water.
Dialysis was used to separate bulk excess salt. RP column was subsequently used to remove excess salt. Ion-exchange column was used to replace possible Mn2+
counter ions into Na s ions. 11 mg (97%) of dark green solid product was obtained. ESI
MS
found m/z= 451.5048 ((MP"), calcd for C88H481\18018S6Mn24" , m/z = 451.5047.
UV-vis (HEPES buffer, pH =7.0) Aabs = 382, 402, 421, 469, 569, 602 nm.
(e) The synthesis of 5,10,15,20-tetrakis(ethoxycarbonyl)porphyrin, 11.
The procedure was performed with a slight modification of the literature method.24 Ethyl *oxalate (50 % in toluene, 1.88 ml, 9.4 mmol) in dichloromethane and pyrrole (0.65 ml, 9.4 mmol) were stirred at room temperature, in the dark and under an argon atmo-sphere. After 10 min BF3.0Et2 (42 ml, 3.10mmol) was added drop wise. The reaction was stirred at room temperature for 1.25 h followed by the addition of MX) (1.5999 g, 7.05 mmol). After a stirring period of 2.25 h NEt3 (0.43 ml, 3.06 mmol) was added via syringe and the reaction mixture was concentrated on a rotary evaporator. The crude solution was suction filtered over sealite using DCM as an elution solvent.
The solution was concentrated on a rotary evaporator. Purification by column chromatography (DCM) on silica gel gave 169.2 mg (12 %) of compound 7 as a black-purple solid. 1H
NMR (500 MHz, CDCI3) 9.52 (811, s, pot-0), 5.11 (8H, q, J = 7.2 Hz), 1.81(12H, t, J =
7.2 Hz), -3.33 (2H, s, NH). UV-vis (DCM) Amax = 409 nm.
(f) The synthesis of [5,10,15,20-tetrakis(ethoxycarbonyl)porphyrinatolmanganese(III) chloride, Mn-11, The current step was performed according to the literature method.24 Compound (17.8 mg, 29.7 pmol) was dissolved in 2 ml of DMF. MnC12.4H20 (17.7mg, 89.2 pmol) was added and the reaction was refluxed open to air for 5 h. The reaction was stirred at room temperature open to air for a further 11.5 h. Distillation of DMF
resulted in a black-purple solid. Purification by stepped gradient column chromatography (eluting with DCM
to 7 % Me0H in DCM) on silica gel gave 16.5 mg (85 /0) of compound Mn-11 as a black-purple solid. ESI MS found miz = 651.1 ([10) , calcd for C32H28MriN408+, m/z =
651.1. UV-vis (Me0H) ¨alas 328, 366, 387, 413, 456, 552 nm.
(g) Synthesis of [5,10,15,20-tetrakis(carboxy)porphyrinato}manganese(III) chloride, MnTCP.
Ethanol (10 ml) and 2 M Na011(a,4) (10 ml) were added to a solution of 7(14.3 mg, 21.9 pmol ) in 6 ml of THF. The reaction was refluxed for 12 h followed by neutralization with 3 M H2S040co. Purification by sephadex LH-20 chromatography with ultrapure water gave the desired product in 85 % yield. ESI MS found m/z = 539.0030 pin, calcd for C24H12MnN408+, m/z = 539.0034. UV-vis (Hepes buffer, pH = 7.0) )tabs = 325, 377, 397, 421, 465, 561, 592 nm.

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Claims (20)

WHAT IS CLAIMED IS:

1. A water soluble porphyrin compound of formula (A), or a salt thereof:
wherein:
each of R1 to R8 and D, E, F and G is independently selected from the group consisting of:
hydrogen; halogen; thiol; cyano; nitro; carboxyl; sulfonate; phosphate (-OPO3H2); alkylphosphate (-OPO3RH); phosphonate (-PO3H2);
alkylphosphonate (-PO3RH); phosphinate (-PO2H); alkylphosphinate (-PO2R);
amino; alkylamino (-NHR); dialkylamino (-NR2); alkylammonium (-NR3+);
aminoalkyl (-(C1-C20 alkyl)NH2); guanidine (-NHC(NH)NH2); alkyl guanidine (-NHC(NH)NRH); amido (-C(O)NH2);
a C3-C20 cycloalkyl group containing a nitrogen atom in its ring wherein the cycloalkyl group is bonded to the porphyrin ring by a carbon or nitrogen atom;

a C3-C20 aryl group containing a nitrogen atom in its ring;
wherein n is from 1 to 20;
wherein n is from 1 to 20;
C1-C20 alkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O), carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C3-C20 cycloalkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O), carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C3-C20 heterocycloalkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O) , carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C2-C20 alkenyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O) , carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C3-C20 cycloalkenyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O) , carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C3-C20 heterocycloalkenyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O) , carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C6 to C20 aryl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C3 to C20 heteroaryl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C7 to C20 arylalkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O) , carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C4 to C20 heteroarylalkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O) , carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C2 to C20 alkynyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O) , carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C1 to C20 heteroalkyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O) , carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2);
C2 to C20 heteroalkenyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O), carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C20 alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2); and C2 to C20 heteroalkynyl, optionally substituted with up to 4 of any of hydroxyl,halogen, thiol, cyano, nitro, oxo (=O) , carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), amino, alkylamino (-NHR), dialkylamino (-NR2), aminoalkyl (-(C1-C2o alkyl)NH2), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH), and amido (-C(O)NH2), wherein each R is independently straight chain or branched C1-C2o alkyl, wherein at least two of D, E, F and G is carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), guanidine (-NHC(NH)NH2), or alkyl guanidine (-NHC(NH)NRH), and wherein M is a paramagnetic metal ion.

2. A compound as claimed in claim 1, or a salt thereof, wherein:
each of D, E, F and G is selected from the group consisting of:
carboxyl, sulfonate, phosphate (-OPO3H2), alkylphosphate (-OPO3RH), phosphonate (-PO3H2), alkylphosphonate (-PO3RH), phosphinate (-PO2H), alkylphosphinate (-PO2R), alkylammonium (-NR3+), guanidine (-NHC(NH)NH2), alkyl guanidine (-NHC(NH)NRH),

3. A compound as claimed in claim 2, or a salt thereof, wherein:
each of D, E, F and G is carboxyl;
each of R1 to R8 is hydrogen; and M is manganese.

4. A pharmaceutical formulation comprising a compound or salt thereof, as claimed in any one of claims 1 to 3 and a pharmaceutically acceptable carrier, wherein the formulation is suited for administration as an imaging enhancing agent and a contrast agent is present in an amount sufficient to enhance a magnetic resonance image.

5. A method of generating an image of at least a part of a subject, the method comprising administering a compound or salt thereof, as claimed in any one of claims 1 to 3, to a subject, and generating an image of at least a part of said subject to which said compound has been distributed.

6. A method of imaging a tumor and surrounding tissue in a subject comprising administering to the subject a composition comprising a compound or salt thereof, as claimed in any one of claims 1 to 3, and imaging the tumor and surrounding tissue in said subject.

7. A composition comprising a compound or salt thereof, as claimed in any one of claims 1 to 3, and a pharmaceutically acceptable carrier, excipient or diluent, suited for administration to a subject.

8. A method for imaging a patient, the method comprising, administering a composition comprising a compound or salt thereof, as claimed in any one of claims 1 to 3, as a blood-pool imaging agent, and a pharmaceutically acceptable carrier, excipient or diluent, and obtaining a magnetic resonance angiography (MRA).

9. A method of detecting a condition in which cells express a characteristic surface protein, the method comprising administering to the cells a contrast agent comprising a compound or salt thereof as defined in any one of claims 1 to 3, coupled to an agent which binds to said protein, and obtaining an MRI image of the cells.

10. The method of claim 9 wherein said condition is lung disease, emphysema, asthma, a cancer, ischemia, chronic kidney disease, or liver disease.

11. The method of claim 10 wherein said cancer is breast cancer, prostate cancer or brain cancer, said ischemia is stroke, cardiac infarct or muscle ischemia, and said chronic kidney disease is cirrhosis or cancer of the liver.

12. The method of any one of claims 9 to 11, comprising administering the contrast agent to cells in vivo.

13. The method of any one of claims 9 to 11, comprising administering the contrast agent to cells in vitro.

14. A method for monitoring transport of an effector agent to a target found within a cell, comprising contacting the cell with a delivery vehicle encapsulating the agent and a contrast agent comprising a compound or salt thereof as defined in any one of claims 1 to 3, and obtaining an MRI image of the cell.

15. The method of claim 14, wherein the delivery vehicle is a nanoparticle, a nanocapsule or a liposome.

16. A method of labeling a cell, the method comprising administering to the cell a contrast agent comprising a compound or salt thereof as defined in any one of claims 1 to 3, coupled to an agent which binds to cell.

17. The method of claim 16, further comprising detecting the labeled cell by obtaining an MRI image thereof.

18. The method of claim 16 or 17, wherein the agent is an antibody.

19. A method of screening for therapeutic agents useful in the treatment of a disease, the method comprising contacting a molecule comprising a test compound coupled to a contrast agent comprising a compound or salt thereof as defined in any one of claims 1 to 3, and contacting the molecule with a target cell, and detecting the labeled cell by obtaining an MRI image thereof.

20. Use of a compound or salt thereof as defined in any one of claims 1 to 3, as a contrast agent.