Novel bispidine-based metal chelating ligands displaying good relaxivity

Abstract

The present invention relates to a novel bispidine-based metal chelating ligand comprising several bispidol compounds covalently linked to each other via a specific linker, each bispidol compound comprising at the N7-position of the bispidine scaffold at least one substituted ethanoic acid or methyl 5 phosphonic acid moiety, said bispidine-based metal chelating ligand being able to form metallic complexes having good properties in terms of relaxivity, to a complex comprising several metal ions complexed with said bispidine-based metal chelating ligand, and to the use of said bispidine-based metal chelating ligand in the field of medical imaging or therapy, and more specifically as MRI10 (magnetic resonance imaging) contrast agents and / or nuclear imaging agents for PET (positron emission tomography) or SPECT (single photon emission tomography).

Description

[0001] NOVEL BISPIDINE-BASED METAL CHELATING LIGANDS DISPLAYING GOOD RELAXIVITY

[0002] The present invention relates to a novel bispidine-based metal chelating ligand comprising several bispidol compounds covalently linked to each other via a specific linker, each bispidol compound comprising at the N7-position of the bispidine scaffold at least one substituted ethanoic acid or methyl phosphonic acid moiety, said bispidine-based metal chelating ligand being able to form metallic complexes having good properties in terms of relaxivity, to a complex comprising several metal ions complexed with said bispidine-based metal chelating ligand. The present invention relates also to the use of said bispidine-based metal chelating ligand in the field of medical imaging or therapy, and more specifically as MRI (magnetic resonance imaging) contrast agents and / or nuclear imaging agents for PET (positron emission tomography) or SPECT (single photon emission tomography).

[0003] Gadolinium-complexes have been used in millions of human examinations with magnetic resonance imaging (MRI) and are considered among the safest diagnostic drugs. The following gadolinium-based contrast agents (GBCAs) have been approved for clinical use: gadopentetate dimeglumine or [Gd(OH2)(dtpa)]2“ (Magnevist®, compound "a" in Scheme 1 below), gadoteridol (ProHance®), gadodiamide or [Gd(OH2)(dtpa-bma)] (Omniscan®, compound "b" in Scheme 1 below), gadoterate meglumine or [Gd(OH2)(dota)] (Dotarem®, compound "c" in Scheme 1 below), gadobutrol or [Gd(OH2)(do3a-butrol)] (Gadovist®, compound "d" in Scheme 1 below), gadoversetamide (OptiMARK®), gadoxetic acid (Primovist®), gadobenate dimeglumine or [Gd(OH2)(bopta)]2“ (MultiHance®, compound e in Scheme 1 below), and gadofosveset trisodium (Vasovist® / Ablavar®).

[0004]

[0005] However, the recent emergence of nephrogenic systemic fibrosis and its causal link to Gd exposure, as well as the evidence on brain and bone accumulation of Gd have alerted the medical community. Nephrogenic systemic fibrosis (NSF) is a rare and serious syndrome that is associated with the exposure to GBCAs in patients with chronic kidney disease. NSF involves fibrotic changes in the skin and many organs and can be a lethal disease.

[0006] Therefore, in 2010, the U.S. Food and Drug Administration (FDA) published revised labelling recommendations for four linear GBCAs which have been principally implicated in NSF, including gadodiamide (Omniscan®), gadobenate dimeglumine (MultiHance®), gadopentetate dimeglumine (Magnevist®), and gadoversetamide (OptiMARK®). In 2017, the European Medicines Agency has decided to stop marketing linear GBCAs contrast agents.

[0007] Furthermore, the negative outcome of using high quantities of Gd(III) based contrast agents, e.g. gadolinium accumulating in surface waters and coming from clinical waste waters, also arises an increasing environmental problem.

[0008] In this context, providing novel Gd(III) based contrast agents that can be administered in lower quantities and / or that are more stable as well as replacing Gd(III) with more biocompatible, safer paramagnetic metal ions have become major objectives.

[0009] Indeed, due to the low sensitivity of MRI as an imaging technique, large quantities of a contrast agent, often on the gram scale, must be injected into the patient to obtain useful images. The ability to reduce the quantity of GBCAs required is highly desirable, especially when considering the toxicity problems discussed above. One way in which the amount of contrast agent required can be reduced is to enhance its relaxivity. Relaxivity is the ability of the metal chelate to relax water protons, and is defined as the change in the relaxation rate of water divided by the millimolar concentration of the chelate. High relaxivities are indicative of more effective agents. All the commercially available GBCAs are very similar to each other in terms of relaxivity. As an example, Dotarem® displays a relaxivity n of 3.7 mM'Ts'1at pH of 7.4, 60 MHz, and 25°C.

[0010] Another way to reduce or avoid the risks of health problems associated with Gd3+release is to provide stable GBCAs. Gd3+release by GBCAs can be characterised by thermodynamic stability and kinetic inertness. Thermodynamic stability refers to the Gibbs free energy involved in the complexation reaction and is defined by the stability constant log K (also called log / <GdL, log / (therm and log Kst). Kinetic inertness refers to complex dissociation rate and is mainly reported as ti / 2, where ti / 2 is defined as the time required for half of the GBCA's dissociation.

[0011] Research is also focused on providing alternative gadolinium(III)-free metal complexes. For example, US2020 / 157099 Al describes Mn(II), Fe(II), Fe(III), Co(II) and Ni(II) ion macrocycle-based complexes to apply as MRI contrast agents and52Mn-based PET diagnostic. The compound responding to the following formula: is complexed with Mn(II) so as to form a Mn(III) macrocycle metal complex [Mn(tPC2AMPyp)]2+having a relaxivity n of 4.90 mM'Ts'1at pH of 7.4 and 25°C and an half-life ti / 2 of complex dissociation calculated at physiologic pH of 352 hours. However, the kinetic inertness of the complex is not completely satisfactory.

[0012] Mangafodipir trisodium (Mn-DPDP), a contrast agent free of Gd(III), was marketed in the 1990's under the tradename Teslascan® comprising Mn(II) ion as the central paramagnetic ion. However, it was withdrawn from the US market in 2003 and from the EU market in 2010 due to low sales, poor clinical performance, and concerns over toxicity. Accordingly, there is a need of novel metal chelating ligands able to form complexes with other metals than gadolinium(III) and which have improved relaxivity while guaranteeing good kinetic inertness and good solubility. Thus, the aim of the present invention is to overcome the drawbacks of the cited prior art, and more particularly, to provide novel metal chelating ligands having good relaxation properties, low toxicity and / or which can be easily eliminated by renal route, water solubility, good kinetic inertness and low dissociation rate. A first object of the present invention is thus a bispidine-based metal chelating ligand responding to the following formula (I): L-(R)n (I) wherein n represents an integer such as n ≥ 2, and R groups represent, independently from each other, ^ a group R1-(T1)r-CH2*-, in which T1represents a C1-C10 alkylene group, and r represents an integer 0 or 1; and / or ^ a group responding to the following formula (II): in which: - T2represents a C1-C10 alkylene group, - A represents -CH2- or -NH-, - X represents an oxygen atom, a sulfur atom, or a NH group, and - s represents an integer 0 or 1 when A represents -CH2- and s represents an integer 1 when A represents -NH-, and wherein * indicates the point of attachment of said group R with L, wherein R1is a bispidol group of the following formula (III):

[0013] in which: - R2represents a PO3H2 group or a CO2H group, - R3and R4, which may be identical or different, represent a CO2H group or a CH2OH group, - R5represents a hydrogen atom, an alkyl group, or a group of formula (IV): –T3-CO2H (IV) where T3represents a C1-C5 alkylene group, - R6, R7, R8, R9, R10, R11, R12, and R13, independently from each other, represent a hydrogen atom, an OH group, an ether group OR14where R14is an alkyl group, a CO2H group, or a CONHR15group, where R15represents an alkyl group, - when r, respectively s, represents an integer 1, * indicates the point of attachment of said group R1with T1, respectively with T2, and when r, respectively s, represents an integer 0, * indicates the point of attachment of said group R1with -CH2-, respectively with -A-; wherein L is at least a divalent linker selected from: ^ a single bond, ^ a guanidine group, ^ an urea group, ^ a thiourea group, ^ a C5-C18 aryl group, ^ a C2-C18 heteroaryl group, ^ a C2-C10 alkyl, a group responding to formula (V) :

[0014] *NH-D(NH*)t-NH* (V) in which D is selected from an aryl group, an heteroaryl group, an alkyl group, a 3-cyclobutene-l, 2-dione group, a polyethylene group, and a polyaminoacid group, and t is an integer ranging from 0 to 6,

[0015] • a group responding to the following formula (VI):

[0016] *NH-(CR15R17)mi-[NR20-(CR18R19)qi]pi-NH* (VI) in which:

[0017] - R16and R17represent, independently from each other, independently at each occurrence ml, a hydrogen atom or a C1-C5 alkyl group,

[0018] - ml is an integer ranging from 2 to 5,

[0019] - R18and R19represent, independently from each other, independently at each occurrence ql, independently at each occurrence pl, a hydrogen atom or a C1-C5 alkyl group,

[0020] - R20represents, independently at each occurrence pl, a hydrogen atom, a C1-C5 alkyl group, a group -T4-NH* in which T4represents a C2-C5 alkylene group, or a single bond*,

[0021] - ql represents, independently at each occurrence pl, an integer ranging from 2 to 5, and

[0022] - pl is an integer ranging from 0 to 4,

[0023] • a group responding to the following formula (VII):

[0024] *E-NH-(CR16R17)mi-[NR21-(CR18R19)qi]Pi-NH-E* (VII) in which:

[0025] - R16, R17, R18, and R19are as defined above,

[0026] - ml, ql, and pl are as defined above,

[0027] - R21represents, independently at each occurrence pl, a hydrogen atom, a C1-C5 alkyl group, a group -T5-NH-E* in which T5represents a C2-C5 alkylene group, or a single bond*, - E is a 3-amino-, or 4-amino-3-cyclobutene-l, 2-dione group, or a C1-C5 alkyl group,

[0028] • a group responding to the following formula (VIII):

[0029] *(CR22R23)m2-NR28-[(CR24R25)q2-NR29]p2-(CR26R27)m3* (VIII) in which :

[0030] - R22and R23represent, independently from each other, independently at each occurrence m2, a hydrogen atom or a C1-C5 alkyl group,

[0031] - m2 is an integer ranging from 1 to 5,

[0032] - R24and R25represent, independently from each other, independently at each occurrence q2, independently at each occurrence p2, a hydrogen atom or a C1-C5 alkyl group,

[0033] - R26and R27represent, independently from each other, independently at each occurrence m3, a hydrogen atom or a C1-C5 alkyl group,

[0034] - m3 is an integer ranging from 1 to 5,

[0035] - R28represents a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*,

[0036] - R29represents, independently at each occurrence p2, a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, a single bond*, or a -[(CR24R25)q2- N R29]P2-(CR26R27) mS* group,

[0037] - q2 represents, independently at each occurrence p2, an integer ranging from 2 to 5, and

[0038] - p2 is an integer ranging from 0 to 4,

[0039] • a group responding to the following formula (IX) :

[0040] *(CR30R31)m4-NR34-[(CH2-CH2-O)q4-CH2-CH2-NR35]p4-(CR32R33)m5* (IX) in which :

[0041] - R30and R31represent, independently from each other, independently at each occurrence m4, a hydrogen atom or a C1-C5 alkyl group,

[0042] - m4 is an integer ranging from 1 to 5, - R32and R33represent, independently from each other, independently at each occurrence m5, a hydrogen atom or a C1-C5 alkyl group,

[0043] - m5 is an integer ranging from 1 to 5,

[0044] - R34represents a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*,

[0045] - R35represents, independently at each occurrence p4, a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*,

[0046] - q4 represents, independently at each occurrence p4, an integer ranging from 1 to 5, and

[0047] - p4 is an integer ranging from 0 to 4, wherein * in formulae (V) to (IX) indicates the possible points of attachment of said linker L with groups R,

[0048] • a polyazacycloalkane saturated group in which at least two -N- functions represent points of attachment of said linker L with groups R,

[0049] • a polyaminoacid group in which at least two functions represent points of attachment of said linker L with groups R, said function being a carbonyl function (derived from the carboxylic acid function) a thiol function, or an amine function,

[0050] • a polyamidoamine group in which at least two -NH- functions represent points of attachment of said linker L with groups R.

[0051] Thus, the ligand of the invention can lead to a metal complex having good relaxation properties, low toxicity and / or which can be easily eliminated by renal route, water solubility, good improved kinetic inertness and low dissociation rate.

[0052] The present invention also includes salts of said bispidine-based metal chelating ligand responding to formula (I).

[0053] Bispidines are chelators based on a 3,7-diazabicyclo[3.3.1]nonane scaffold. The bispidine scaffold is formed by two fused cyclohexylamine rings.

[0054] More particularly, the bispidol groups R1of formula (III) present in the metal chelating ligand (I) of the present invention have a so-called 2,4- disubstituted bispidol core and their IUPAC numbering is presented as follows:

[0055]

[0056] Said bispidol group R1of formula (III) is expected to coordinate at least in a pentadentate manner, involving two pyridine and two bispidine nitrogens as well as the methylene carboxylate moiety or the methylene phosphonate moiety at the N7 position. Additionally the ligand of the present invention comprises several bispidol groups R1of formula (III) linked to each other through appropriate chemical groups linked to the methylene carboxylate or phosphonate moiety -CH*-R2, i.e. appropriate L linkers and appropriate T1, T2, A, X groups within the R groups leading to improved relaxivity with similar coordination and hence kinetic inertness or dissociation rate.

[0057] The bispidine-based metal chelating ligands of the present invention are highly preorganized ligands that can accommodate several metal ions with cis- octahedral, square-pyramidal, or pentagonal geometries. The bispidine-based metal chelating ligands of the invention form thermodynamically very stable metal complexes with transition-metal ions, and in particular with Mn(II), which show high relaxivity. Modification of the coordinating pendant arms can be used to tune the ligand denticity as well as all electronic, thermodynamic, and kinetic parameters such as the ligand field, the metal selectivity, and the stability constants. Such properties are very appealing for applications in diagnosis as chelators for metals other than gadolinium, and more specifically for manganese and copper metals, as well as radiometals such as64Cu,52Mn and67Ga.

[0058] In the present invention, the term "alkyl group" refers to a saturated linear, branched, or cyclic (branched or unbranched) hydrocarbon chain, generally comprising from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 4 carbon atoms. In the present invention, alkyl groups may be monovalent or polyvalent (i.e., alkylene groups are encompassed in "alkyl" definition).

[0059] In the present invention, the term "alkylene group" refers to a divalent alkyl group.

[0060] In the present invention, the term "aryl group" refers to a cyclic, polyunsaturated, aromatic hydrocarbyl group comprising at least one aromatic ring and comprising from 5 to 20 carbon atoms, preferably from 5 to 18 carbon atoms. Aryl groups may have a single ring or multiple aromatic rings fused together or linked covalently.

[0061] In the present invention, the terms "Cx-Cy" or "(Cx-Cy)" preceding the name of a group means that the group comprises from x to y carbon atoms, in accordance to common terminology in the chemistry field.

[0062] In the present invention, the term "heteroaryl" refers to cyclic, polyunsaturated, aromatic hydrocarbyl group comprising at least one aromatic ring and comprising from 2 to 20 carbon atoms, preferably from 2 to 18 carbon atoms, having one or two rings which are fused together or linked covalently, wherein one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulfur atoms. The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.

[0063] The bispidol group R1of formula (III)

[0064] The bispidol group R1of formula (III) is either covalently linked to T1in the group R1-(T1)r-CH2*- when r represents an integer 1, or covalently linked to CH2in the group RHT^r-CHz*- when r represents an integer 0.

[0065] The bispidol group R1of formula (III) is either covalently linked to T2in the group R1-(T2)S-A-C(=X)*- when s represents an integer 1, or covalently linked to A in the group R1-(T2)S-A-C(=X)*- when s represents an integer 0.

[0066] The R2group

[0067] R2represents a PO3H2 group or a CO2H group, and preferably a CO2H group.

[0068] The R3and R4groups R3and R4, which may be identical or different, represent a CO2H group or a CH2OH group.

[0069] R3and R4are preferably identical.

[0070] In one preferred embodiment, R3and R4represent CO2H groups.

[0071] The R5group

[0072] R5represents a hydrogen atom, an alkyl group, or a group of formula (IV) : -T3-CO2H (IV) where T3represents a C1-C5 alkylene group, preferably an alkyl group or a group of formula (IV): -T3-CO2H (IV) where T3represents a Ci- Cs alkylene group, and more preferably an alkyl group.

[0073] The alkyl group as R5can be a linear or a branched alkyl group, and preferably a linear alkyl group.

[0074] In the present invention, the term "linear" means an unsubstituted or unbranched.

[0075] The alkyl group as R5is preferably a C1-C5 alkyl group, and more preferably a methyl group.

[0076] In one particularly preferred embodiment, R5is a linear C1-C5 alkyl group.

[0077] In the group of formula (IV): -T3-CO2H (IV), T3represents a C1-C5 alkylene group.

[0078] In the present invention, the term "alkylene" means an alkyl group which is divalent. The term "alkyl" means a saturated aliphatic hydrocarbon radical.

[0079] In the present invention, the term "aliphatic hydrocarbon radical" means a hydrocarbonated chain and the term "aliphatic" is opposed to "aromatic".

[0080] The C1-C5 alkylene group as T3can be a linear or a branched alkylene group, and preferably a linear alkylene group.

[0081] T3preferably represents a C1-C3 alkylene group.

[0082] The R6, R7, R8, R9, R10, R11, R12, and R13groups

[0083] R6, R7, R8, R9, R10, R11, R12, and R13, independently from each other, represent a hydrogen atom, an OH group, an ether group OR14where R14is an alkyl group, a CO2H group, or a CONHR15group, where R15represents an alkyl group. The alkyl group as R14can be a linear or a branched alkyl group, and preferably a linear alkyl group.

[0084] The alkyl group as R14is preferably a C1-C10 alkyl group, and more preferably a C1-C5 alkyl group, and even more preferably a methyl or ethyl group.

[0085] The alkyl group as R15can be a linear, branched, or cyclic alkyl group, and preferably a linear or cyclic alkyl group.

[0086] The alkyl group as R15is preferably a C1-C20 alkyl group, more preferably a C1-C12 alkyl group, and even more preferably a Ci-Ce alkyl group.

[0087] In one preferred embodiment, at least R7and R11, and / or R9and R13represent hydrogen atoms. In other words, the pyridine rings can be substituted in 4 and / or 6 positions (i.e. at least R5and R10, and / or R8and R12are different from hydrogen atoms).

[0088] In one particularly preferred embodiment, R6, R7, R8, R9, R10, R11, R12, and R13groups represent hydrogen atoms.

[0089] In one preferred embodiment, which can be advantageously combined with the preceding preferred embodiments, R6and R10are identical, R7and R11are identical, R8and R12are identical, and / or R9and R13are identical, and more preferably R6and R10are identical, R7and R11are identical, R8and R12are identical, and R9and R13are identical.

[0090] The R group

[0091] L is at least a divalent linker. A divalent linker means that the linker is covalently linked to at least two chemical elements. In the ligand of the present invention, the linker L is covalently linked or bounded to at least two groups R (n > 2) (L is at least a divalent linker). As a result, when the linker L is a chemical group, at least two groups R are linked to said linker L and when the linker L is a single bond, two groups R are covalently linked via said single bond.

[0092] In one preferred embodiment, 2 < n < 8, preferably 2 < n < 6, and more preferably 2 < n < 4.

[0093] A group R is preferably linked to the linker L through (via) a function selected from an amide function (-NH(C=O)- or -(C=O)NH-), an urea function (-NH(C=O)NH-), a thiourea (-NH(C=S)NH-), a guanidine function (- NH(C=NH)NH-), or an amine function (-NH-). In that embodiment, the function can be provided either by the linker L, the group R or both the linker and the group R.

[0094] The R groups are either groups R^T^r-CHz*-, groups of formula (II) R1- (T2)s-A-C(=X)*-, or mixture thereof, and preferably groups of formula (II) R1- (T2)S-A-C(=X)*-.

[0095] The group RMT^r-CHz*- r represents an integer 0 (i.e. T1absent) or 1 (i.e. T1present).

[0096] The Ci-Cio alkylene group as T1can be a linear or a branched alkylene group, and preferably a linear alkylene group.

[0097] T1preferably represents a Ci-Cs alkylene group, and more preferably a C1-C4 alkylene group.

[0098] In one advantageous embodiment of the present invention, the R group RHT^r-CHz*- is covalently linked to L via an -NH- function, a guanidine function or an urea function. In the former embodiment, the linker L may be a group responding to formula (V) and in the latter embodiments, the linker L may be a guanidine group and a urea group respectively.

[0099] The group of formula (II) R1-(T2)S-A-C(=X)*- s represents an integer 0 (i.e. T2absent) or 1 (i.e. T2present).

[0100] T2represents a C1-C10 alkylene group.

[0101] The C1-C10 alkylene group can be a branched or a linear alkylene group, and preferably a linear alkylene group.

[0102] T2preferably represents a Ci-Cs alkylene group, more preferably a Ci-Ce alkylene group, and even more preferably a C2-C6 alkylene group.

[0103] The following embodiments for the group of formula (II) are particularly advantageous:

[0104] - A represents -NH- and X represents an oxygen atom,

[0105] - A represents -NH- and X represents a sulfur atom,

[0106] - A represents -NH- and X represents a NH group,

[0107] - A represents -CH2-, and X represents an oxygen atom. In one advantageous embodiment of the present invention, the R group R1-(T2)S-A-C(=X)*- is covalently linked to L via an amide function (-NH(C=O)- or -(C=O)NH-), a urea (-NH(C=O)NH-) or an thiourea function (-NH(C=S)NH- ). In that embodiment, the linker L may be a Cs-Cis aryl group, a C2-C18 heteroaryl group, a C2-C10 alkyl group, a polyazacycloalkane saturated group, a polyaminoacid group, or any group responding to formula (V), (VI), (VII), (VIII), (IX) as defined below.

[0108] The embodiment where A represents -NH- and X represents an oxygen atom or a sulfur atom is more particularly advantageous.

[0109] The linker L

[0110] The linker L is at least a divalent linker and enables covalent linking of groups R to each other via said linker L.

[0111] Since L is at least a divalent linker, it comprises at least two points of attachment (mentioned by the asterisk *) so as to covalently link / bind said linker L to said groups R. In the present invention, when the linker L comprises more than two possible points of attachments of said linker L with groups R, the possible points of attachments in excess of two can either be used as points of attachment of said linker L with groups R or be attached to a hydrogen atom.

[0112] The linker L can be a single bond.

[0113] In that embodiment, groups R are directly bounded together. For example, a group R responding to formula R1-(T1)r-CH2*- is attached to another group R responding to formula R1-(T1)r-CH2*- so as to form the ligand R1-^1)^ CH2-CH2-(T1)r-R1, or a group R responding to formula R1-(T1)r-CH2*- is attached to a group R responding to formula (II): R1-(T2)S-A-C(=X)*- so as to form the ligand R1-(T1)r-CH2-C(=X)-A-(T2)s-R1; or a group R responding to formula (II): R1-(T2)S-A-C(=X)*- is attached to another group R responding to formula (II): R1-(T2)S-A-C(=X)*- so as to form the ligand R1-(T2)S-A-C(=X)-C(=X)-A-(T2)S- R1.

[0114] In that embodiment, preferred examples of ligands are the followings:

[0115] * R1-(T1)r-CH2-C(=O)-A-(T2)s-R1,

[0116] * R1-(T2)s-A-C( = O)-C( = O)-A-(T2)s-R1.

[0117] The linker L can be a guanidine group. This embodiment is particularly advantageous when groups R respond to formula R1-(T1)r-CH2*-.

[0118] The linker L can be a urea group.

[0119] This embodiment is particularly advantageous when groups R respond to formula R1-(T1)r-CH2*-.

[0120] The linker L can be a thiourea group.

[0121] This embodiment is particularly advantageous when groups R respond to formula R1-(T1)r-CH2*-.

[0122] The linker L can be a Cs-Cis aryl group.

[0123] In the present invention, the term "Cs-Cis aryl" refers to aromatic rings or aromatic ring systems comprising from 5 to 18 carbon atoms, having one or two rings which are fused together or linked covalently, wherein at least one ring is aromatic.

[0124] The Cs-Cis aryl group can be selected from a phenyl group, an anthracene group, a fluorene group and a naphthyl group, and preferably a phenyl group.

[0125] The Cs-Cis aryl group can be substituted with one or more W substituents, preferably selected from hydroxyl, ether, primary and secondary amine, carboxylic acid, amide, nitro, and thiol substituents.

[0126] The Cs-Cis aryl group is preferably a C5-C12 aryl group.

[0127] The linker L can be a C2-C18 heteroaryl group.

[0128] In the present invention, the term "C2-C18 heteroaryl" refers to aromatic rings or aromatic ring systems comprising from 2 to 18 carbon atoms, having one or two rings which are fused together or linked covalently, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings is replaced by heteroatom(s), preferably selected from an oxygen atom, a nitrogen atom, a sulfur atom, and mixture thereof.

[0129] The C2-C18 heteroaryl group can be selected from pyridine, diazine, pyrimidine, guinoline, indole, indazole, furan, oxazoline, pyrrole, pyrazole, pyrazine, pyridazine, cinnoline, phthalazine, quinazoline, quinaxoline, triazine, triazole, thiophene, porphyrine, aryl-based cyanine, and other aryl-based dyes, and preferably 1,3,5-triazine group and 1,2,3-triazole group. The C2-C18 heteroaryl group can be substituted with one or more W substituents, preferably selected from hydroxyl, ether, primary and secondary amine, carboxylic acid, amide, nitro, and thiol substituents.

[0130] The C2-C18 heteroaryl group is preferably a C2-C12 heteroaryl group.

[0131] The linker L can be a C2-C10 alkyl group.

[0132] The C2-C10 alkyl group as L can be a linear, branched or cyclic alkyl group.

[0133] The C2-C10 alkyl group is preferably a C2-C6 alkyl group, and even more preferably a C2-C4 alkyl group.

[0134] The C2-C10 alkyl group can be substituted with one or more groups selected from hydroxyl group, aminoacid group, and mixture thereof.

[0135] The aminoacid group may be selected from lysine, ornithine, arginine, histidine, aspartic acid, glutamic acid, tryptophan, and cysteine.

[0136] Examples of C2-C10 alkyl groups are the followings: wherein * represent the points of attachment of the linker L to the group R.

[0137] The linker L can be a group responding to formula fVT

[0138] *NH-D(NH*)t-NH* (V) in which D is selected from an aryl group, an heteroaryl group, an alkyl group, a 3-cyclobutene-l, 2-dione group, a polyethylene group, and a polyaminoacid group, and t is an integer ranging from 0 to 6, preferably t is an integer ranging from 0 to 4, and more preferably t is an integer ranging from 0 to 2.

[0139] In formula (V), * indicates the possible points of attachment of said linker L with groups R.

[0140] The aryl group as group D can be a C5-C18 aryl group, and preferably a C5-C12 aryl group. The aryl group can be selected from a phenyl group and a naphthyl group, and preferably a phenyl group.

[0141] The aryl group can be substituted with one or more W substituents, preferably selected from hydroxyl, ether, primary and secondary amine, carboxylic acid, amide, nitro, and thiol substituents.

[0142] The heteroaryl as group D can be a C2-C18 heteroaryl group, and preferably a C2-C12 heteroaryl group.

[0143] The heteroaryl group can be selected from pyridine, diazine, pyrimidine, quinoline, indole, indazole, furan, oxazoline, pyrrole, pyrazole, pyrazine, pyridazine, cinnoline, phthalazine, quinazoline, quinaxoline, triazine, triazole, thiophene, porphyrin, aryl-based cyanine, and other aryl-based dyes, and preferably 1,3,5-triazine group and 1,2,3-triazole group.

[0144] The heteroaryl group can be substituted with one or more W substituents, preferably selected from hydroxyl, ether, primary and secondary amine, carboxylic acid, amide, nitro, and thiol substituents.

[0145] The alkyl group as group D can be a C2-C16 alkyl group, and preferably a C2-C10 alkyl group.

[0146] The alkyl group can be a linear, branched or cyclic alkyl group, and preferably a linear or cyclic alkyl group.

[0147] The alkyl group can be selected from cyclooctyl, cycloheptyl, cyclohexyl, cyclopentyl, adamantane, bicyclo[2.2.1]heptane, ethyl, and preferably cyclohexyl and adamantane.

[0148] The polyethylene group as group D can comprise several branches of -- OCH2CH2- moieties. In a particular embodiment, the polyethylene group comprises from 5 to 25 carbon atoms, and preferably from 7 to 19 carbon atoms.

[0149] The polyaminoacid group as group D comprises at least two amine functions that represent in formula (V) possible points of attachment of said linker L with groups R.

[0150] The polyamino acid group can be a polylysine group. In one preferred embodiment, the linker L responds to any one of the following formula (V): wherein * represent the possible points of attachment of the linker L to the group R.

[0151] The linker L can be a group responding to the following formula (VI):

[0152] *NH-(CR15R17)mi-[NR20-(CR18R19)qi]Pi-NH* (VI) in which:

[0153] - R16and R17represent, independently from each other, independently at each occurrence ml, a hydrogen atom or a C1-C5 alkyl group,

[0154] - ml is an integer ranging from 2 to 5, preferably ranging from 2 to 4,

[0155] - R18and R19represent, independently from each other, independently at each occurrence gl, independently at each occurrence pl, a hydrogen atom or a C1-C5 alkyl group, - R20represents, independently at each occurrence pl, a hydrogen atom, a C1-C5 alkyl group, a group -T4-NH*- in which T4represents a C2-C5 alkylene group, or a single bond*, - ql represents, independently at each occurrence pl, an integer ranging from 2 to 5, and

[0156] - pl is an integer ranging from 0 to 4, and preferably pl is an integer ranging from 1 to 4.

[0157] In formula (VI), * indicates the possible points of attachment of said linker L with groups R.

[0158] R16, R17, R18, R19and R20groups

[0159] The C1-C5 alkyl group as R16group (respectively as R17, R18, R19or R20group) can be a linear alkyl group or a branched alkyl group, and preferably a linear alkyl group.

[0160] The C1-C5 alkyl group is preferably a C1-C3 alkyl group, and more preferably a methyl or ethyl group.

[0161] The C2-C5 alkylene group as T4can be a linear or branched alkylene group, and preferably a linear alkylene group.

[0162] The C2-C5 alkylene group as T4is preferably a C2-C4 alkylene group.

[0163] When R20is a single bond, the nitrogen to which R20is attached is directly linked to a group R.

[0164] In one preferred embodiment, R20represents, independently at each occurrence pl, a hydrogen atom or a group -T4-NH*-.

[0165] At least one of R15and R17groups is preferably a hydrogen atom, both R16and R17groups are more preferably hydrogen atoms.

[0166] For all occurrences ml, the groups CR16R17are preferably identical.

[0167] At least one of R18and R19groups is preferably a hydrogen atom, both R18and R19groups are more preferably hydrogen atoms.

[0168] For all occurrences ql, the groups CR18R19are preferably identical.

[0169] In the linker L of formula (VI), there may be alternation of a radical - [NR20-(CR18R19)qi] where R20represents a hydrogen atom, and of a radical - [NR20-(CR18R19)qi] where R20represents a group -T4-NH*-.

[0170] In one particular preferred embodiment, the linker L responds to the any one of the following formula (VI) :

[0171] wherein * represent the possible points of attachment of the linker L to the group R.

[0172] The linker L can be a group responding to the following formula (VII): *E-NH-(CR16R17)mi-[NR21-(CR18R19)qi]Pi-NH-E* (VII) in which:

[0173] - R16, R17, R18, and R19are as defined above,

[0174] - ml, ql, and pl are as defined above,

[0175] - R21represents, independently at each occurrence pl, a hydrogen atom, a C1-C5 alkyl group, a group -T5-NH-E* in which T5represents a C2-C5 alkylene group, or a single bond*,

[0176] - E is a 3-amino-, or 4-amino-3-cyclobutene-l, 2-dione group, or a C1-C5 alkyl group.

[0177] In formula (VII), * indicates the points of attachment of said linker L with groups R.

[0178] R21group The C1-C5 alkyl group as R21group can be a linear alkyl group or a branched alkyl group, and preferably a linear alkyl group.

[0179] The C1-C5 alkyl group is preferably a C1-C3 alkyl group, and more preferably a methyl or ethyl group.

[0180] The C2-C5 alkylene group as T5can be a linear or branched alkylene group, and preferably a linear alkylene group.

[0181] The C2-C5 alkylene group as T5is preferably a C2-C4 alkylene group.

[0182] When R21is a single bond, the nitrogen to which R21is attached is directly linked to a group R.

[0183] In one preferred embodiment, R21represents, independently at each occurrence pl, a hydrogen atom or a group -T5-NH-E*.

[0184] In the linker L of formula (VII), there may be alternation of a radical - [NR21-(CR18R19)qi] where R21represents a hydrogen atom, and of a radical - [NR21-(CR18R19)qi] where R21represents a group -T5-NH-E*.

[0185] E group

[0186] The C1-C5 alkyl group as E group can be a linear alkyl group or a branched alkyl group, and preferably a linear alkyl group.

[0187] The C1-C5 alkyl group is preferably a C1-C3 alkyl group, and more preferably a methyl or ethyl group.

[0188] In one particular preferred embodiment, the linker L responds to any one of the following formula (VII) : wherein * represent the possible points of attachment of the linker L to the group R. The linker L can be a group responding to the following formula (VIII) : *(CR.22R23)m2-NR.28-[(CR.24R25)q2-NR29]p2-(CR26R.27)m3* (VIII) in which :

[0189] - R22and R23represent, independently from each other, independently at each occurrence m2, a hydrogen atom or a C1-C5 alkyl group,

[0190] - m2 is an integer ranging from 1 to 5,

[0191] - R24and R25represent, independently from each other, independently at each occurrence q2, independently at each occurrence p2, a hydrogen atom or a C1-C5 alkyl group,

[0192] - R26and R27represent, independently from each other, independently at each occurrence m3, a hydrogen atom or a C1-C5 alkyl group,

[0193] - m3 is an integer ranging from 1 to 5,

[0194] - R28represents a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*,

[0195] - R29represents, independently at each occurrence p2, a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, a single bond*, or a -[(CR24R25)q2- NR29]P2-(CR26R27)m3* group,

[0196] - q2 represents, independently at each occurrence p2, an integer ranging from 2 to 5, and

[0197] - p2 is an integer ranging from 0 to 4.

[0198] In formulae (VIII), * indicates the possible points of attachment of said linker L with groups R.

[0199] R22, R23, R24, R25, R26, R27, R28and R29groups

[0200] The C1-C5 alkyl group as R22group (respectively as R23, R24, R25, R25, R27, R28or R29group) can be a linear alkyl group or a branched alkyl group, and preferably a linear alkyl group.

[0201] The C1-C5 alkyl group is preferably a C1-C3 alkyl group, and more preferably a methyl or ethyl group.

[0202] When R28(respectively R29) is a single bond, the nitrogen to which R28(respectively R29) is attached is directly linked to a group R. In one preferred embodiment, R28represents a hydrogen atom or a Ci- Cs alkylene group*.

[0203] In one preferred embodiment, R29represents, independently at each occurrence p2, a hydrogen atom or a C1-C5 alkylene group*. At least one of R22and R23groups is preferably a hydrogen atom, both

[0204] R22and R23groups are more preferably hydrogen atoms.

[0205] For all occurrences m2, the groups CR22R23are preferably identical.

[0206] At least one of R24and R25groups is preferably a hydrogen atom, both R24and R25groups are more preferably hydrogen atoms. For all occurrences q2, the groups CR24R25are preferably identical.

[0207] At least one of R25and R27groups is preferably a hydrogen atom, both R26and R27groups are more preferably hydrogen atoms.

[0208] For all occurrences m3, the groups CR26R27are preferably identical.

[0209] In the linker L of formula (VIII), the radical [(CR24R25)q2-NR29] may be identical for all occurrences p2, preferably with R29representing a C1-C5 alkylene group*.

[0210] In one particularly preferred embodiment, the linker L responds to any one the following formula (VIII): wherein * indicates the possible points of attachment of said linker L with groups R.

[0211] The linker L can be a group responding to the following formula (IX): *(CR30R31)m4-NR34-[(CH2-CH2-O)q4-CH2-CH2-NR35]P4-(CR32R33)m5* (IX) in which :

[0212] - R30and R31represent, independently from each other, independently at each occurrence m4, a hydrogen atom or a C1-C5 alkyl group,

[0213] - m4 is an integer ranging from 1 to 5,

[0214] - R32and R33represent, independently from each other, independently at each occurrence m5, a hydrogen atom or a C1-C5 alkyl group,

[0215] - m5 is an integer ranging from 1 to 5,

[0216] - R34represents a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*,

[0217] - R35represents, independently at each occurrence p4, a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*,

[0218] - q4 represents, independently at each occurrence p4, an integer ranging from 1 to 5, and

[0219] - p4 is an integer ranging from 0 to 4.

[0220] In formula (IX), * indicates the points of attachment of said linker L with groups R.

[0221] R30, R31, R32, R33, R34, and R35groups

[0222] The C1-C5 alkyl group as R30group (respectively as R31, R32, R33, R34, or R35group) can be a linear alkyl group or a branched alkyl group, and preferably a linear alkyl group.

[0223] The C1-C5 alkyl group is preferably a C1-C3 alkyl group, and more preferably a methyl or ethyl group.

[0224] When R34(respectively R35) is a single bond, the nitrogen to which R34(respectively R35) is attached is directly linked to a group R.

[0225] In one preferred embodiment, R34represents a hydrogen atom or a Ci- Cs alkylene group*. In one preferred embodiment, R35represents, independently at each occurrence p4, a hydrogen atom or a C1-C5 alkylene group*.

[0226] At least one of R30and R31groups is preferably a hydrogen atom, both R30and R31groups are more preferably hydrogen atoms.

[0227] For all occurrences m4, the groups CR30R31are preferably identical.

[0228] At least one of R32and R33groups is preferably a hydrogen atom, both R32and R33groups are more preferably hydrogen atoms.

[0229] For all occurrences m5, the groups CR32R33are preferably identical.

[0230] In one particularly preferred embodiment, the linker L responds to the following formula (IX): wherein * indicates the possible points of attachment of said linker L with groups.

[0231] The linker L can be a polyazacycloalkane saturated group in which at least two -N- functions of attachment of said linker L with

[0232] R. The ne saturated group can "free" -N- i.e. not linked to said R so that they are in the form of -NH functions, which the that at least two amino functions are linked / bounded to R gr

[0233] The polyazacycloalkane saturated group as linker L can be selected from cyclen, cyclam, and derivatives thereof. Such compounds are polyazamacrocyclic compounds. In particular, cyclen represents 1,4,7,10- tetraazacyclododecane and cyclam represents 1,4,8,11- tetraazacyclotetradecane.

[0234] The polyazacycloalkane saturated group can comprise from 3 to 25 carbon atoms, and preferably from 4 to 15 carbon atoms. The polyazacycloalkane saturated group as linker L has preferably at least three, and more preferably at least for -N- functions represent points of attachment of said linker L with groups R.

[0235] In particular, the polyazacycloalkane saturated group as linker L can respond to any one of the following formulae: wherein * indicates the possible points of attachment of said linker L with groups.

[0236] As an example, said latter linker can have one -N- function in excess of two which is not attached to a group R according to the following formula: wherein * indicates the points of attachment of said linker L with groups.

[0237] The linker L can be a polyaminoacid group in which at least two functions represent points of attachment of said linker L with groups R, said function being a carbonyl function Cderived from the carboxylic acid function), a thiol function, or an amine function.

[0238] These functions are "free" functions or pending functions within the polyaminoacid (i.e. not participating to the polymerization involving reaction of an amino function with a carboxylic acid function so as to form said polyaminoacid).

[0239] The polyaminoacid group may comprise several aminoacid selected from lysine, ornithine, arginine, histidine, aspartic acid, glutamic acid, tryptophan, and cysteine. Examples of such polyaminoacid groups are the ones based on polyglutamic acid (PGA) or aspartic acid, such as the following one based on aspartic acid : wherein * indicates the possible points of attachment of said linker L with groups.

[0240] The linker L can be a polyamidoamine group.

[0241] A poly(amidoamine) group is also called a PAMAM group. It is a class of dendrimer which is made of repetitively branched subunits of amide and amine functionality.

[0242] In one preferred embodiment, the poly(amidoamine) group responds to the following formula: wherein * indicates the possible points of attachment of said linker L with groups.The linker L is preferably a C5-C18 aryl group such as a phenyl group or any group responding to formula (V), (VI) or (VIII). In one particularly preferred embodiment of the present invention, the ligand is selected from the following formulae (I-a) to (I-n) and salts thereof:

[0243]

[0244] A second object of the present invention is a complex of a metal M, wherein said complex comprises several metal ions of said metal M complexed with a bispidine-based metal chelating ligand (I) as defined in the first object of the present invention, said metal M being selected from copper, manganese, gallium, cobalt, zinc, nickel, and iron, and preferably selected from copper and manganese.

[0245] The metal M can be radioactive.

[0246] The metal ion can be selected from Mn2+, Mn3+, Cu2+, Cu+, Ga3+, Co2+, Co3+, Fe2+, Fe3+, Zn2+, or Ni2+.

[0247] The complex of the present invention exhibits high relaxivity, show a favourable pharmacokinetic profile, is completely excreted, is chemically stable, exhibit high water solubility, offer the possibility of providing safe alternatives to traditional GBCAs and offer the potential for a significant dose reduction in comparison to state-of-the-art Mn-based contrast agents (CAs), and is suitable for imaging of different body regions.

[0248] A third object of the present invention is the use of a bispidine-based metal chelating ligand (I) as defined in the first object of the present invention or a complex as defined in the second object of the present invention, in the field of medical imaging or therapy, and more specifically as MRI (magnetic resonance imaging) contrast agents and / or nuclear imaging agents for PET (positron emission tomography) or SPECT (single photon emission tomography).

[0249] Positron emission tomography (PET) is a highly sensitive imaging technique with high tissue penetration. This technique can allow for the in vivo imaging of diseased tissues by targeting biochemical processes; thus allowing for detection of disease before physical changes occur.

[0250] More particularly, the bispidine-based metal chelating ligand (I) as defined in the first object of the present invention can be used as a chelator for radioactive copper for application in immuno-positron emission tomography (PET).

[0251] More particularly, the bispidine-based metal chelating ligand (I) as defined in the first object of the present invention can be used as bifunctional chelating agents for HER2+ immuno-imaging of breast cancer or for PET immuno-imaging of multiple myeloma, for radioimmunotherapy or again as a theragnostic probe combining therapy and diagnostic.

[0252] The present invention is illustrated in more detail in the examples below, but it is not limited to said examples.

[0253] Examples

[0254] Solvents and starting materials were purchased from Aldrich, Acros and Alfa Aesar and used without further purification. IR spectra were recorded on a Perkin Elmer Spectrum One Spectrophotometer as solid samples and only the most significant absorption bands are given in cm4. Elemental analyses and mass spectrometry analyses were carried out by the Service Commun d'Analyses of the University of Strasbourg.XH and13C NMR spectra and 2D COSY, NOESY, HSQC, and HMBC experiments were recorded on Avance 300 and Avance 400 spectrometers operating at 7.04 T and 9.39 T, respectively. Chemical shifts are reported in ppm, with residual protonated solvent as internal reference.

[0255] Example 1 : synthesis of intermediate compound 4

[0256] Compound 4 was prepared according to the following scheme 1 :

[0257] Pl is a well-known starting material to lead to bispidone and bispidine compounds.

[0258] Bispidone 1. In a solution of methanol (60 mL), Ne-Boc-L-lysine (4.19 g, 17.40 mmol) and NaHCCh (1.46 g, 17.40 mmol) were mixed under stirring during Ih at 45°C. Then, formaldehyde (3.5 mL, 47.50 mmol) and precursor Pl (6.06 g, 15.80 mmol) in methanol (20 mL) were added at room temperature (rt) and the mixture was stirred under reflux during 5h. At the end of the reaction, the solution was filtered and solvents were removed under reduced pressure. The obtained solid was dissolved in a minimum of methanol and was precipitated upon dropwise addition in a large amount of diethyl ether. After centrifugation, precipitates were collected and dried to give a pure beige solid (6.93 g, 67%).

[0259] TLC (AI2O3; DCM / MeOH, 85 / 15); Rf = 0.5.1H-NMR (400 MHz, CDCl3): δ 8.95 (m, 2H, Ha+Ha’), 7.70 (t, J= 7.6 Hz, 1H, Hc’), 7.59 (t, J= 7.5 Hz, 1H, Hc), 7.35 (m, 1H, Hb’), 7.17 (m, 3H, Hd’+Hd+Hb), 4.67 (s, 1H, H2), 4.56 (s, 1H, H4), 3.81 (broad s, 1H, COOH), 3.77 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.22 (AB system, δA = 3.60, δB = 2.84, JAB = 12.0 Hz, νA = 1440 Hz, νB = 1136 Hz, 2H, H8 / H6), 2.96 (AB system, δA = 3.29, δB = 2.62, JAB = 12.0 Hz, νA = 1316 Hz, νB = 1048 Hz, 2H, H8 / H6), 2.99 (m, 2H, H14), 2.57 (d, 1H, H10), 1.86 (s, 3H, CH3), 1.64-1.22 (m, 15H, H11 / H12 / H13 / OC(CH3)3). 13C-NMR (100 MHz, CDCl3): δ 202.7 (C9), 177.0 (COOH), 168.0 (COOMe), 167.5 (COOMe), 156.1 (3C, 1Cpy+Cpy’+COOtBu), 151.5 (Ca / Ca’), 151.1 (Ca / Ca’), 137.5 (Cc / Cc’), 137.0 (Cc / Cc’), 124.5 (Cb / Cb’ / Cd / Cd’), 124.2 (Cb / Cb’ / Cd / Cd’), 124.0 (Cb / Cb’ / Cd / Cd’), 121.7 (Cb / Cb’ / Cd / Cd’), 78.7 (C(OCH3)3), 74.0 (C10), 72.6 (2C, C2+C4), 63.0 (2C, C1+C5), 57.5 (C6 / C8), 54.7 (C6 / C8), 52.8 (OCH3), 52.5 (OCH3), 43.0 (CH3), 40.3 (C14), 29.9 (C11), 28.9 (C13), 28.5 (C(CH3)3), 24.0 (C12). IR (cm-1, ATR) ^ 3366 (broad, N-H amide), 2943, 2860 (broad, O-H acid), 1739 (s, C=O ester), 1695 (s, C=O acid), 1572 (s, C=C aromatic), 1254 (s, C- O). Electrospray ionization ESI / MS+: m / z = 654.31 ([M+H]+, 100%), 655.31 ([M+H]+, 35.7%), 656.32 ([M+H]+, 6.2%), 657.32 ([M+H]+, 0.7%). Bispidol 2. Bispidone 1 (3.08 g, 4.71 mmol) was dissolved in anhydrous methanol (110 mL) and was cooled at -77°C on a bath of acetone / dry ice. Then, sodium borohydride (240.00 mg, 7.07 mmol) was slowly added. After 6h at - 77°C, the mixture was placed at 4°C for one night. Then NH4Cl (520.00 mg, 9.72 mmol) was added in the flask and the mixture was stirred during 10 minutes. Solvents were removed under reduced pressure and the obtained solid was purified by flash chromatography column (reverse phase, CH3CN / H2O 20 / 80-25 / 75). The pure compound 2.2H2O was obtained as a white solid (1.10 g, 32%). TLC (SiO2; DCM / MeOH, 80 / 20); Rf = 0.3-0.5. 1H-NMR (400 MHz, MeOD): δ 8.67 (m, 2H, Ha+Ha’), 7.81 (m, 2H, Hc+Hc’), 7.60 (m, 2H, Hd+Hd’), 7.38 (m, 2H, Hb+Hb’), 4.89 (s, 2H, H2+H4), 4.50 (s, 1H, H9), 4.30 (AB system, δA = 4.60, δB = 4.00, JAB = 12.0 Hz, 2H, H6 / H8), 3.96 (AB system, δA = 4.10, δB = 3.91, JAB = 12.0 Hz, 2H, H6 / H8), 3.76 (m, 1H, H10), 3.63 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 3.08 (m, 2H, H14), 2.33-2.17 (m, 2H, H11), 1.73 (m, 4H, H12+H13), 1.65 (s, 3H, CH3), 1.39 (s, 9H, C(CH3)3). 13C-NMR (75 MHz, MeOD): δ 172.8 (COOH), 170.4 (2C, COOMe), 158.3 (COOtBu / Cpy / Cpy’), 157.8 (COOtBu / Cpy / Cpy’), 157.7 (COOtBu / Cpy / Cpy’), 150.6 (Ca / Ca’), 150.1 (Ca / Ca’), 138.1 (Cc / Cc’), 138.0 (Cc / Cc’), 128.6 (2C, Cd+Cd’), 124.9 (Cb / Cb’), 124.8 (Cb / Cb’), 79.7 (C(CH3)3), 73.8 (C9), 72.0 (C10), 67.8 (C2 / C4), 67.5 (C2 / C4), 56.8 (C8 / C6), 53.0 (OCH3), 52.9 (OCH3), 52.3 (2C, C1+C5), 51.2 (8 / 6), 41.6 (CH3), 41.1 (C14), 30.7 (C13), 30.0 (C11), 28.7 (C(CH3)3), 25.1 (C12). Electrospray ionization ESI / MS+: m / z = 656.33 ([M+H]+, 100%), 657.34 ([M+H]+, 35.7%), 658.34 ([M+H]+, 3.5%). Elemental analysis calculated for C33H45O9N5.1.5H2O: C, 58.05, H, 7.09, N, 10.26. Found: C, 57.82, H, 6.81, N, 10.38. Bispidol 3. Bispidol 2 (413.0 mg, 0.74 mmol) was dissolved in CH2Cl2 (8 mL) and trifluoroacetic acid (2 mL) and the mixture was stirred at room temperature. After 3h, solvents were evaporated under reduced pressure and the crude TFA salt was used in the next step without purification (413 mg). TLC (C18; CH3CN / H2O, 0.1% TFA, 50 / 50); Rf = 0.8. 1H-NMR (400 MHz, MeOD): δ 8.76 (m, 2H, Ha+Ha’), 7.94 (m, 2H, Hc+Hc’), 7.77 (m, 2H, Hd+Hd’), 7.52 (m, 2H, Hb+Hb’), 5.63 (s, 1H, H2 / H4), 5.61 (s, 1H, H2 / H4), 4.41 (s, 1H, H9), 3.72 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.33 (AB system, δA = 3.52, δB = 3.13, JAB = 12.0 Hz, νA = 1408 Hz, νB = 1252 Hz, 2H, H6 / H8), 3.39 (AB system, δA = 3.41, δB = 3.38, JAB = 10.5 Hz, νA = 1363 Hz, νB = 1353 Hz, 1H, H10), 3.13 (m, 2H, H6 / H8), 3.03 (t, J= 8.5Hz, 2H, H14), 2.35-1.92 (m, 2H, H11), 2.31 (s, 3H, CH3), 1.90 (m, 2H, H13), 1.61 (m, 2H, H12). 13CNMR (75 MHz, D2O): δ 173.6 (COOH), 170.5 (COOMe), 170.4 (COOMe), 152.9 (Cpy / Cpy’), 152.8 (Cpy / Cpy’), 151.0 (Ca / Ca’), 150.4 (Ca / Ca’), 139.1 (Cc / Cc’), 139.0 (Cc / Cc’), 129.0 (Cd / Cd’), 128.6 (Cd / Cd’), 126.2 (Cb / Cb’), 126.1 (Cb / Cb’), 73.9 (C9), 68.1 (C10), 67.6 (C2 / C4), 67.1 (C2 / C4), 55.8 (C6 / C8), 54.4 (C1 / C5), 53.7 (C1 / C5), 53.3 (OCH3), 53.2 (OCH3), 50.4 (C6 / C8), 43.4 (CH3), 40.7 (C14), 29.8 (C11), 28.8 (C13), 25.0 (C12). Compound 4. Bispidol 3 (279.0 mg, 0.50 mmol) was dissolved in a mixture of H2O / THF (8 mL / 2 mL) and sodium hydroxide (240.0 mg, 3.0 mmol) as added at room temperature under stirring. After 48h, the mixture was vaporated under reduced pressure and was purified by column hromatography (reverse phase, 100% H2O to 100% MeOH in 15 min). Pure compound 4.2Na (265.0 mg, 71%) was obtained as a white powder. TLC (C18; CH3CN / H2O, 20 / 80), Rf = 0.4. 1H-NMR (400 MHz, D2O): δ 8.48 (m, 2H, Ha+Ha’), 7.54 (m, 2H, Hc+Hc’), 30 (d, J= 9.0 Hz, 1H, Hd / Hd’), 7.19 (m, 1H, Hd / Hd’), 7.14 (m, 2H, Hb+Hb’), 40 (s, 1H, H2 / H4), 4.31 (s, 1H, H2 / H4), 3.82 (s, 1H, H9), 2.42 (AB system, = 2.92, δB = 1.93, JAB = 12.3 Hz, νA = 1167 Hz, νB = 774 Hz, 2H, H6 / H8), 36 (t, J= 6.9 Hz, 2H, H14), 2.29 (AB system, δA = 2.75, δB = 1.83, JAB = 11.2 z, νA = 1102 Hz, νB = 731 Hz, 2H, H6 / H8), 2.20 (m, 1H, H10), 1.51 (s, 3H, H3), 1.47-1.36 (m, 2H, H11), 1.20 (m, 2H, H13), 1.10 (m, 2H, H12). 13C-NMR (100 MHz, D2O): δ 181.4 (COOH), 179.1 (COOH), 178.6 COOH), 159.9 (Cpy / Cpy’), 159.3 (Cpy / Cpy’), 149.2 (2C, Ca+Ca’), 137.0 (2C, c+Cc’), 126.0 (Cd / Cd’), 125.5 (Cd / Cd’), 122.9 (Cb / Cb’), 122.8 (Cb / Cb’), 75.3 C10), 74.3 (C9), 67.8 (C2 / C4), 67.1 (C2 / C4), 55.9 (C6 / C8), 53.3 (C5 / C8), 1.7 (C1 / C5), 51.5 (C1 / C5), 42.8 (CH3), 40.2 (C14), 32.0 (C13), 29.6 (C11), 3.0 (C12). IR (cm-1, ATR) ^ 3342 (broad, O-H alcohol / N-H amine), 2949 (broad, O- acid), 1584, 1568 (s, C=C aromatic / N-H amine), 1366 (s, C-O). Electrospray ionization ESI / MS+: m / z = 528.25 ([M+H]+, 100%), 529.25 M+H]+, 28.1%), 530.25 ([M+H]+, 3.8%). Elemental analysis calculated for C26H31O7N5Na2.3H2O: C, 49.91, H, 5.96, 11.19. Found: C, 49.79, H, 5.92, N, 11.19. Example 2: synthesis of compound (I-a) Compound (I-a) was prepared according to the following scheme 2:

[0260] Compound 5. Compound 3 (191.3 mg, 0.25 mmol) is dissolved in 15 ml of CH3CN. Triethylamine (0.153 ml, 1.1 mmol) is then added and the mixture is placed under argon. Succinyl chloride (14.4 mmol, 0.088 mmol) in 5 ml of CH3CN is added dropwise to the mixture under argon and the middle is stirred at 80 °C for 16 hours. At the end the solvent is evaporated and the crude product is purified on SPOT II FPLC (C18, CH3CN / H2O, 0.1% TFA) to give 5 (104 mg) with 83% yields. 1H NMR (MeOD, 400 MHz): δ 8.77 (m, 4H, Ha+Ha’), 7.93 (m, 4H Hc + Hc’), 7.75 (m, 4H, Hd + Hd’), 7.52 (m, 4H, Hb + Hb’), 5.62 (s, 2H, H2 / H4), 5.60 (s, 2H, H2 / H4), 4.40 (s, 2H, H9), 3.71 (s, 6H, OCH3), 3.68 (s, 6H, OCH3), 3.54 (d, J = 12.4 Hz, 2H, H6 / H8), 3.37 (dd, J = 10.1, 4.4 Hz, 2H, H10) , 3.26 (m, 4H, H14), 3.12 (m, 6H, H6 / H8), 2.51 (s, 4H, H16), 2.29 (m, 8H, H15 + H11 / H11’), 1.86 (m, 2H, H11 / 11’), 1.71 (m, 4H, H13), 1.54 (m, 4H, H12). Compound (I-a). Compound 5 (104 mg, 0.073 mmol) and LiOH (33 mg, 1.38 mmol are dissolved in 15 ml of H2O. The mixture was stirred for 16 hours at room temperature. At the end the solvent is evaporated. The crude product was dissolved in a minimum of water and the pH was adjusted to 2 and the solution was purified on SPOT II FPLC (C18, CH3CN / H2O, 0.1% TFA) to give compound (I-a) with 83% yield. 1H NMR (MeOD, 400 MHz): δ 8.77 (m, 4H, Ha+Ha’), 7.91 (m, 4H Hc + Hc’), 7.76 (m, 4H, Hd + Hd’), 7.50 (m, 4H, Hb + Hb’), 5.57 (s, 2H, H2 / H4), 5.55 (s, 2H, H2 / H4), 4.40 (s, 2H, H9), 3.46 (m, 2H, H6 / H8), 3.35 (m, 2H, H10), 3.27 (m, 4H, H14), 3.07 (m, 6H, H6 / H8), 2.51 (s, 4H, H16), 2.30 (m, 8H, H15 + H11 / H11’), 1.84 (m, 2H, H11 / 11’), 1.70 (m, 4H, H13), 1.54 (m, 4H, H12). 13C NMR (MeOD, 126 MHz): δ 174.68, 173.82, 171.78, 171.63, 153.24, 153.16, 150.85, 150.33, 138.91, 138.79, 129.12, 128.76, 126.01, 74.07, 68.40, 67.84, 67.32, 56.28, 53.31, 52.79, 50.44, 43.41, 40.42, 32.41, 30.53, 29.94, 25.38. Electrospray ionization ESI / MS-: m / z = 1135.48 ([M - H]-, 100%), 1136.48 ([M - H]-, 75%), 1137.48 ([M - H]-, 29%), ([M - H]-, 8 %), 567.23 ([M - 2H]2-, 100%), 567.73 [M - 2H]2-, 68%), 568.23 ([M - 2H]2-, 26%), 568.73 ([M - 2H]2-, 5%). Example 3: synthesis of compound (I-b) Compound (I-b) was prepared according to the following scheme 3: SCHEME 3 Compound 6. Compound 3 (72.4 mg, 0.061 mmol) and DIPEA (0.083 µl, 0.48 mmol) are dissolved in ACN (10 ml) and the middle is placed under argon. Diethyl squarate (16.1 mg 0.095 mmol) dissolved in a minimum of ACN is then added end the reaction is heated at 50 °C for 2 hours. Compound 3 (113 mg, 0.15 mmol) and DIPEA (0.12 µl, 0.69 mmol) a second time and the temperature is increased to 80 °C and heated overnight. At the end of the reaction the solvent is removed under vacuum. The crude product is finally purified on C18 (H2O, ACN, 0.1% TFA) to give compound 6 (15 mg). 1H NMR (500 MHz, MeOD): δ 8.75 (m, 4H, Ha + Ha’), 7.91 (m, 4H, Hc + Hc’), 7.72 (m, 4H, Hd + Hd’), 7.49 (m, 4H, Hb + Hb’), 5.58 (s, 2H, H2 + H4) 5.57 (s, 2H, H2 + H4), 4.39 (s, 2H, H9), 3.67 (m, 14H, OCH3 + H14), 3.61 (m, 2H, H6 + H8), 3.40 (dd, J1= 9.1, J2= 5.3 Hz, 2H, H10), 3.14 (m, 6H, H6 + H8), 2.33 (m, 2H, H11 / 11’), 2.27 (s, 6H, H15), 1.86 (m, 6H, H11 / 11’ + H13) 1.69 (m, 2H, H12 / H12’), 1.61 (m, 2H, H12 / H12’). 13C NMR (126 MHz, MeOD): δ 173.69, 170.45, 170.36, 169.44, 153.06, 152.91, 150.96, 150.51, 138.93, 138.83, 129.03, 128.70, 126.14, 126.09, 74.01, 68.37, 67.76, 67.20, 56.16, 53.69, 53.28, 53.21, 50.29, 45.19, 43.19, 32.50, 29.82, 25.19. MALDI-MS: m / z = calculated for C60H72N10O16 [M+] 1188.51, found 1188.14. Compound (I-b). Compound 6 (15 mg, 0.013 mmol) and LiOH (6 mg, 0.25 mmol) were dissolved in 3 ml of water. The mixture was stirred at room temperature for 3 days. At the end, the solvent was removed under vacuum. The crude product was dissolved in a minimum of water and the pH was adjusted to 2 and purified on C18 (H2O / ACN, 0.1% TFA) to give compound (I- b) (9 mg) with 64% yields. 1H NMR (400 MHz, MeOD): δ 8.74 (td, J1 = 7.8, J2 = 1.8 Hz, 4H, Ha + Ha’), 7.90 (m, 4H, Hc + Hc’), 7.76 (m, 4H, Hd + Hd’), 7.49 (m, 4H, Hb + Hb’), 5.56 (s, 2H, H2 + H4), 5.54 (s, 2H, H2 + H4), 4.42 (s, 2H, H9), 3.73 (m, 4H, H14), 3.54 (dd, J1 = 12.4, J2 = 2.1 Hz, 2H, H6 + H8), 3.38 (dd, J1 = 9.3, J2 = 5.0 Hz, 2H, H10), 3.10 (m, 6H, H6 + H8), 2.33 (m, 8H, H15 + H11 / 11’) 1.86 (m, 6H, H11 / 11’ + H13), 1.65 (m, 4H, H12 / H12’). 13C NMR (101 MHz, MeOD): δ 172.29, 169.04, 168.95, 168.04, 151.66, 151.50, 149.56, 149.11, 137.53, 137.42, 124.73, 124.69, 116.75, 114.46, 72.61, 66.97, 66.35, 65.79, 54.75, 52.22, 51.94, 51.36, 48.89, 43.84, 41.91, 31.15, 28.50, 23.77. MALDI-MS: m / z = calculated for C56H64N10O16 [M+] 1132.45, found 1132.14. Example 4: synthesis of compound (I-c) Compound (I-c) was prepared according to the following scheme 4: N N Compound 7. Compound 3 (58 mg, 8.68x10-5mol, 2.3 eq.) was suspended in 2 mL of DCM. P-phenyl diisothiocyanate (7 mg, 3.70x10-5mol, 1 eq.) and triethylamine (17.5 µL, 3.62x10-4mol, 10 eq.) were added to the solution. The solution was stirred overnight at room temperature. After stirring, the disappearance of p-phenyl diisothiocyanate was observed by TLC (7 / 3 DCM / MeOH). The solvent was evaporated and the mixture was dissolved in a minimum of MeOH. The precipitation of compound 7 was performed by adding diethyl ether. The precipitate was washed 3 times with diethyl ether to afford 23 mg of a white powder. The precipitate was washed 3 times with diethyl ether to afford 23 mg of a white powder. This mixture was directly used for the synthesis of compound (I)-c without further purification. Compound (I-c). Compound 7 (23 mg, 1.77x10-5mol, 1 eq.) was suspended in 2 mL of a mixture of water and THF 1 / 1. LiOH (7.3 mg, 3.04x10-4mol, 17 eq.) was added in the solution. Compound 7 dissolves thanks to LiOH. The solution was stirred overnight at room temperature. The disappearance of compound 7 was checked by HPLC (H2O 0.1% TFA, ACN 0.1% TFA). The solvent was evaporated and the mixture was purified by preparative HPLC (100% H2O 0.1% TFA to 8 / 2 H2O 0.1% TFA / ACN 0.1% TFA) to afford 24 mg (white powder) of compound (I-c) which was isolated in a form of a TFA salt in a 49% yield over 2 steps. 1H NMR (500 MHz, MeOD): δ 8.82 (m, 4H, Ha +Ha’), 7.90 (tdd, J=7.8, 3.1, 1.8, 4H, Hc + Hc’), 7.77 (m, 4H, Hb + Hb’), 7.55 – 7.43 (m, 4H, Hd + Hd’), 7.32 (s, 4H, He), 5.57 (s, 2H, H2 / H4), 5.59 (s, 2H, H2 / H4), 4.42 (s, 2H, H9), 3.78 – 3.61 (m, 4H, H14), 3.52 (dd, J=12.4, 1.8, 2H, H6 + H8), 3.40 – 3.33 (m, 2H, H10), 3.15 – 3.01 (m, 6H, H6 + H8), 2.37 (m, 2H, H11 / 11’), 2.31 (s, 6H, H15), 1.94 – 1.74 (m, 6H, H13 + H11 / 11’), 1.64 (m, 2H, H12 / 12’), 1.57 (m, 2H, H12 / 12’). 13C NMR (126 MHz, Methanol-d4): δ 181.23 (Cquat), 172.45 (Cquat), 170.42 (Cquat), 170.24 (Cquat), 160.81 (Cquat), 151.83 (Cquat), 151.76 (Cquat), 149.57 (CHar), 149.17 (CHar), 137.43 (CHar), 137.30 (CHar), 127.58 (CHar), 127.25 (CHar), 125.38 (CHar)), 124.60 (CHar), 124.57 (CHar), 72.64 (CH), 67.11 (CH), 66.54 (CH), 65.99 (CH), 55.02 (CH2), 51.90 (Cquat), 51.36 (Cquatz), 48.92 (CH2), 44.26 (CH2), 44.34 (CH2), 42.04 (CH3), 28.89 (CH2), 28.64 (CH2), 24.04 (CH2). Electrospray ionization MS (ESI+, H2O): m / z = 624.24 ([M+2H]2+, 40%), 631.24 ([M+2Li]2+, 100%), 1247.4 ([M+H]+, 1%), 631.24 ([M+2Li]+, 3%). Example 5: synthesis of compound (I-g) Compound (I-g) was prepared according to the following scheme 5:

[0261] Compound 9. Compound 3 (300 mg, 0.37 mmol) and DIPEA (314 µl, 1.8 mmol, 4.86 eq) are dissolved in 40 ml of DMF. Compound 8 (58 mg, 0.37 mmol, 1 eq) is added, and the mixture is stirred for 2 hours at 50 °C. The solvent is removed under vacuum and the crude product is purified by FPLC (C18, H2O / ACN, 0.1% TFA) to give compound 9 with 95% yield. 1H NMR (400 MHz, MeOD): δ 8.78 (m, 6H, Ha); 7.91 (m, 6H, Hc); 7.73 (m, 6H, Hd); 7.50 (m, 6H, Hb); 5.60 (s, 3H, H2 / H4); 5.58 (s, 3H, H2 / H4); 4.38 (s, 3H, H9); 3.82(s, 6H, H16); 3.71 (s, 9H, OCH3); 3.68 (s, 9H, OCH3); 3.54 (m, 3H, H6 / H8); 3.36 (m, 9H, H10 + H14); 3.10 (m, 9H, H6 / H8); 2.29 (m, 12H, H11 / 11’ + H15); 1.86 (m, 3H, H11 / 11’); 1.73 (m, 6H, H13); 1.54 (m, 6H, H12). 13C NMR (126 MHz, MeOD): δ 173.67, 170.47, 170.38, 169.55, 161.62- 158.46 (TFA), 152.98, 152.85, 151.04, 150.51, 139.03, 138.91, 128.93, 128.61, 126.16, 126.13, 118.40-112.65 (TFA), 73.93, 68.27, 67.62, 67.10, 58.40, 55.93, 53.69, 53.33, 53.26, 53.22, 50.32, 43.33, 40.41, 30.45, 29.82, 25.30. Electrospray ionization ESI / MS+: m / z (%) = calculated for C90H115N16O24 [M + H]+1804.82, C90H115N16O24K [M + H + K]2+921.89, C90H116N16O24 [M + 2H]2+902.91, C H N O K [M + 2H + K]3614.93, C H N O [M + 3H]3+ 90 116 16 24+90 117 16 24 602.29, C90H118N16O24K [M + 3H +K]4+461.45. Found 1804.83, 921.90, 902.92, 614.94, 602.29, 461.45. Compound (I-g). Compound 9 (212 mg, 0.1 mmol) is dissolved in 15 ml of water. Lithium hydroxide (56 mg, 2.3 mmol, 23 eq) is then added, and the mixture is stirred at room temperature for 3 days. The reaction is monitored by NMR. At the end of the reaction, the solvent is removed under vacuum and the crude product is purified by FPLC (C18, H2O / ACN, 0.1% TFA) to give compound (I-g) (170 mg) with 68% yield. 1H NMR (400 MHz, MeOD): δ 8.76 (m, 6H, Ha), 7.90 (m, 6H, Hc), 7.50 (m, 6H, Hd), 7.49 (m, 6H, Hb), 5.57 (s, 3H, H2 / H4) 5.55 (s, 3H, H2 / H4), 4.41 (s, 3H, H9), 3.53 (s, 6H, H16), 3.45 (m, 3H, H6 / H8), 3.34 (m, 9H, H10 + H14 ), 3.03 (m, 9H, H6 / H8), 2.30 (m, 12H, H11 / 11’ + H15), 1.75 (m, 9H, H13 + H11 / 11’), 1.54 (m, 6H, H12). 13C NMR (126 MHz, MeOD): δ 173.70, 171.77, 171.60, 162.26, 153.25, 153.15, 150.87, 150.36, 138.87, 138.74, 129.03, 128.68, 126.00, 73.98, 68.37, 67.86, 67.34, 59.04, 56.28, 53.29, 52.77, 50.41, 43.44, 40.32, 30.54, 29.91, 25.34. Electrospray ionization ESI / MS+: m / z (%) = calculated for C84H103N16O24 [M + H]+1720.73, C84H103N16O24K [M + H + K]2+879.34, C84H104N16O24 [M + 2H]2+860.87 , C H N 6O24K [M + 2H + K]3+586.90 C H N O [M + 3H]3+ 84 104 1 84 105 16 24 573.92. Found 1720.71, 879.33, 860.86, 586.89, 573.91. Elemental Analysis: calculated for C84H102N16O24(CF3COOH)5(H2O)5, C, 47.44, H, 4.96, N, 9.42. Found: C, 47.28, H, 4.82, N, 9.60. HPLC (C18Aq Interchim 20 cm, de 95 / 5 H2O / ACN, 0.1 % TFA to 100 ACN 0.1 % TFA in 15 min.) RT = 10.87 min. Example 6: synthesis of a complex of manganese (II) [(I-A)] with bispidine-based metal chelating ligands (I-a) A complex (I-A) of manganese (II) with chelating bispidine-based ligand (I-a) of example 2 (complex Mn2(I-a)) was prepared as follows: 409 µl of a solution of (I-a) at 1.5 mM is mixed to 50 µL of MnCl2 at 98.3 mM solution. MilliQ water is added to reach a volume of 1.5 ml After 30 min at 60 °C the pH was increased from 4 to 7 and the mixture was heated at 60 °C overnight. The end of the reaction is monitored by HPLC. At the end of the reaction, the solvent is removed under vacuum and the crude is purified on HPLC preparative (C18, ACN / H2O, 0.1 % TFA). A solution of 800 µl of (I-A) at 1.59 mM (determined by ICP-AES) is finally obtained. The same preparation method was used to obtain a complex (I-B) of manganese (II) with compound 4, which is not part of the invention. Table 1 below shows the properties of complex (I-A), and for comparison of complex (I-B). Longitudinal relaxivity r1 is expressed per millimolar concentration of complex. Longitudinal relaxivity r1,Mn is expressed per millimolar concentration of Mn(II). * Not part of the invention TABLE 1 Figure 1 represents the NMRD profile (longitudinal relaxivity r1 as a function of proton larmor frequency in mM-1.s-1as a function of the frequency in MHz) of complex (I-A) in water at 25°C (curve with diamonds) and at 37°C (curve with triangles). In the present invention, the relaxivity at 60MHz is measured with a device commercialized under the brand name WP80 NMR by the firm Brucker according to the following protocol. A millimolar aqueous solution of complex was prepared with Milli-Q water (ρ < 18MΩ). The concentration of Mn2+- containing samples was checked by ICP-OES and / or NMR. by using the bulk magnetic susceptibility. The absence of free Mn2+was checked by the Xylenol orange test. For the relaxivity measurement, the temperature was monitored by a VTC91 temperature control unit and maintained by a gas flow. The temperature was determined by previous calibration with a Pt resistance temperature probe.

[0262] Example 7: synthesis of compound (I-h)

[0263] Compound (I-h) was prepared according to the following scheme 6: Compound 10. A mixture of 0.5 ml of thionyl chloride and 5 ml of MeOH is stirred at 0°C for 30 minutes. Then, compound 3 (709 mg, 0.81 mmol, 1 eq) is added and the mixture is stirred at reflux for two days. At the end of the reaction, the solvent is removed under vacuum. The crude product is dissolved in a minimum of water and the pH is adjusted to 3. The solution is purified by FPLC (C18, H2O / ACN, 0.1% TFA) to give compound 10 as a TFA salt (631 mg, 0.79 mmol) with 97% yield. 1H NMR (400 MHz, MeOD): δ 8.76 (m, 2H, Ha), 7.95 (m, 2H, Hc), 7.76 (m, 2H, Hd), 7.53 (m, 2H, Hb), 5.64 (s, 1H, H2 / 4), 5.62 (s, 1H, H2 / 4), 4.38 (s, 1H, H9), 3.74 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.53 (m, 1H, H6 / 8), 3.44 (m, 1H, H11), 3.03 (m, 5H, H6 / 8 + H15), 2.38 (m, 1H, H12 / 12’), 2.32 (s, 3H, H10), 1.91 (m, 3H, H12 / 12’ + H14),1.55 (m, 2H, H13). 13C NMR (126 MHz, MeOD): δ 172.50, 170.37, 170.30, 152.84, 152.73, 151.04, 150.43, 139.14, 139.03, 129.01, 128.71, 126.25, 126.22, 73.78, 68.07, 67.54, 67.05, 55.94, 53.71, 53.37, 53.30, 53.23, 52.02, 50.22, 43.41, 40.72, 30.17, 28.83, 24.99. Electrospray ionization ESI / MS+: m / z (%) = calculated for C29H39N5O7 570.29 [M + H]+, found, 570.29. Compound 11. H4EDTA (13 mg, 0.22 mmol, 1 eq) and DIPEA (92 µl, 0.53 mmol, 12 eq) are added in 15 ml of DMF. The mixture is heated during 20 min at 80 °C until the complete dissolution of H4EDTA. The mixture is cooled at room temperature. Then, HATU (100 mg, 0.26 mmol, 6 eq) is added and the mixture is stirred during 10 min at room temperature. Compound 10 (176 mmol, 0.22 mmol, 4.4 eq) and DIPEA (185 µl, 1.1 mmol, 25 eq) are added and the mixture is stirred at 50 °C for 16 h. At the end of the reaction, the solvent is removed under vacuum and the crude product is purified by FPLC (C18, H2O / CH3CN, 0.1 % TFA) to give compound 11 (50 mg, 0.017 mmol) as a TFA salt with 38% yield. 1H NMR (400 MHz, MeOD): δ 8.75 (m, 8H, Ha), 7.90 (m, 8H, Hc), 7.72 (m, 8H, Hd), 7.54 (m, 8H, Hb), 5.62 (s, 4H, H2 / 4), 5.60 (s, 4H, H2 / 4), 4.37(s, 4H, H9), 3.84 (s, 8H, H16), 3.71 (s, 12H, OCH3), 3.69 (s, 12H, OCH3), 3.67 (s, 12H, OCH3), 3.52 (m, 4H, H6 / 8), 3.40 (m, 4H, H11), 3.33 (m, 8H, H15 + H17), 3.00 (m, 12H, H6 / 8) , 2.30 (m, 15H, H12 / 12’ + H10), 1.80 (m, 12H, H12 / 12’ + H14), 1.47 (m, 8H, H13). 13C NMR (126 MHz, MeOD): δ 172.58, 170.41, 170.31, 169.38, 152.88, 152.76, 151.05, 150.49, 139.10, 138.96, 128.98, 128.68, 126.20, 126.19, 73.84, 68.21, 67.57, 67.08, 57.69, 56.02, 53.70, 53.53, 53.35, 53.29, 53.22, 52.01, 50.24, 43.36, 40.51, 30.46, 30.14, 25.34. Electrospray ionization ESI / MS+: m / z (%) = calculated for C126H164N22O32, 1250.10 [M+2H]2+, 833.74 [M+3H]3+, 625.56 [M+4H]4+. Found 1250.10, 833.73, 625.55. Lithium hydroxide (0.34 mmol, 8 mg, 20 eq) is dissolved in a solution of compound 11 (50 mg, 0.017 mmol) in a mixture of H2O (5 ml) and THF (1 ml) and the reaction is stirred at 50 °C and monitored by HPLC (C18, H2O / CH3CN, 0.1% TFA). Additional amount of LiOH is then added during the reaction as followed: 2 mg (0.08 mmol, 5 eq) after 2 days and 2 mg (0.08 mmol, 5 eq) after 3 days. After 4 days, the reaction is completed. The pH is adjusted to pH = 4 with HCl 1M and the solvent is removed under vacuum. The crude product is purified by FPLC (C18, H2O / CH3CN, 0.1 % TFA) to give compound (I-h) as a TFA salt with 36% yield 1H NMR (400 MHz, MeOD): δ 8.76 (m, 8H, Ha), 7.89 (m, 8H, Hc), 7.77 (m, 8H, Hd), 7.51 (m, 8H, Hb), 5.58 (s, 4H, H2 / 4), 5.56 (s, 4H, H2 / 4), 4.41 (s, 4H, H9), 3.85 (s, 8H, H16), 3.46 (m, 4H, H6 / 8), 3.35 (m, 16 H, H11 + H17 + H15), 3.06 (m, 12H, H6 / 8), 2.30 (m, 16H, H10 + H12 / 12’), 1.82 (m, 12H, H14 + H12 / 12’), 1.50 (m, 12H, H13). 13C NMR (126 MHz, MeOD): δ 173.71, 171.79, 171.60, 169.54, 153.27, 153.17, 150.86, 150.35, 138.90, 138.78, 129.01, 128.70, 126.03, 126.00, 73.97, 68.41, 67.86, 67.36, 57.76, 56.19, 53.44, 53.28, 52.78, 50.55, 43.45, 40.51, 30.48, 29.85, 25.38. Electrospray ionization ESI / MS+: m / z (%) = calculated for C114H140N22O32, 1166.01 [M+2H]2+, 777.67 [M+3H]3+, 583.51 [M+4H]4+. Found 1166.01, 777.67, 583.51. HPLC (C18Aq interchim 20 cm, from 95 / 5 H2O / ACN, 0.1% TFA to 100 CH3CN, 0.1% TFA in 15 min.) R.T. = 11.19 min Example 8: synthesis of compound (I-i)

[0264] Compound (I-j) was prepared according to the following scheme 7:

[0265] Compound 12. Compound 10 (342 mg, 0.43 mmol, 3.3 eq) is dissolved in 20 ml of ACN and DIPEA (2.15 mmol, 374 pl, 16.5 eq) is added. Then, a solution of 1,3,5-benzenecarbonyl trichloride (0.13 mmol, 35 mg, 1 eq) in 5 ml of DMF is added to the mixture and the reaction is stirred for 16 hours at room temperature. At the end of the reaction, the solvent is removed under vacuum and the crude product is purified by FPLC (Cis, H2O / ACN, 0.1% TFA) to give compound 12 as a TFA salt (92 mg, 0.042 mmol) with 32% yield.1H NMR (400 MHz, MeOD): δ 8.76 (m, 6H, Ha), 8.44 (s, 3H, He), 7.90 (m, 6H, Hc), 7.75 (m, 6H, Hd), 7.53 (m, 2H, Hb), 5.62 (s, 3H, H2 / H4), 5.59 (s, 3H, H2 / H4), 4.38 (s, 3H, H9), 3.71 (s, 9H, OCH3), 3.70 (s, 9H, OCH3), 3.68 (s, 9H, OCH3), 3.61 (m, 3H, H6 / H8), 3.52 (m, 6H, H15), 3.46 (m, 3H, H11), 3.06 (m, 9H, H6 / H8), 2.39 (m, 3H, H12 / 12’), 2.30 (s, 9H, H10), 1.90 (m, 9H, H12 / 12’ + H14), 1.65 (m, 6H, H13 / 13’), 1.54 (m, 6H, H13 / 13’). 13C NMR (101 MHz, MeOD): δ 172.69, 170.40, 170.30, 168.51, 152.87, 152.73, 151.04, 150.50, 139.00, 138.88, 136.80, 129.86, 128.97, 128.64, 126.18, 126.13, 73.85, 68.31, 67.64, 67.08, 56.20, 53.70, 53.33, 53.26, 53.18, 51.94, 50.03, 43.30, 41.02, 30.61, 30.29, 25.51. Electrospray ionization ESI / MS+: m / z (%) = calculated for C96H117N15O24, 933.44 [M+2H]2+, 622.63 [M+3H]3+, found 933.44, 622.63. Compound (I-j). Compound 12 (92 mg, 0.042 mmol, 1 eq) is dissolved in a mixture of THF (6 ml) and H2O (10 ml). Lithium hydroxide (18 mg, 0.76 mmol, 18 eq) is added and the mixture is stirred at 50 °C for 16 h. Then 6 mg of LiOH is added and the reaction is stirred at 50°C for 2 days. The reaction is monitored by HPLC on reverse phase (C18). The solvent is removed under vacuum and the crude product is dissolved in a minimum of water and the pH is adjusted to 4. The solution is purified by FPLC (C18, H2O / ACN, 0.1% TFA) to give compound (I-j) as a TFA salt (53 mg, 0.024 mmol) with 56% yield. 1H NMR (400 MHz, MeOD): δ 8.76 (m, 6H, Ha), 8.43 (s, 3H, He), 7.89 (m, 6H, Hc), 7.78(m, 6H, Hd), 7.50 (m, 6H, Hb), 5.58 (s, 3H, H2 / 4), 5.56 (s, 3H, H2 / 4), 4.41 (s, 3H, H9), 3.55 (m, 9H, H6 / 8 + H15), 3.35 (m, 3H, H11), 3.06 (m, 9H, H6 / 8), 2.29 (m, 12H, H12 / 12’ + H10), 1.87 (m, 9H, H14 + H12 / 12’) 1.66 (m, 6H, H13). 13C NMR (101 MHz, MeOD): δ 173.83, 171.76, 171.60, 168.61, 153.23, 153.13, 150.85, 150.35, 138.83, 138.72, 136.82, 129.88, 129.08, 128.72, 126.00, 125.95, 74.05, 68.49, 67.86, 67.32, 56.37, 53.29, 52.75, 50.36, 43.36, 41.09, 30.64, 30.05, 25.56. Electrospray ionization ESI / MS+: m / z (%) = calculated for C96H119N15O24 C87H99N15O24, 1739.71 [M+H]+, 870.36 [M+2H]2+, 580.58, [M+3H]3+. Found 1739.71, 870.36, 580.56. Elemental Analysis: calculated for C87H99N15O24(CF3COOH)4(H2O)5, C, 50.33, H, 4.94, N, 9.27. Found: C, 50.20, H, 5.02, N, 9.42. HPLC (C18Aq Interchim 20 cm, 95 / 5 H2O / ACN, 0.1 % TFA to 100 ACN 0.1% TFA in 15 min) RT = 11.28 min. Example 9: synthesis of intermediate compound 16 Compound 14. NaHCO3 (120 mg, 3.89 mmol, 3 eq) is added to a solution of H-Asp-OMe (286 mg, 1.42 mmol, 1.5 eq) in 50 ml MeOH. The mixture is stirred during 1 h at 45 °C. Then compound 13 (also called P1) (500 mg, 1.3 mmol, 1 eq) and formaldehyde are added (316 µl, 3.9 mmol, 3 eq) and the mixture is stirred for 1 hour at 70°C. At the end of the reaction, the solvent is removed under vacuum and the crude product is dissolved in a minimum of CH3CN. The solution is precipitated in Et2O and the solid is isolated. A yellow powder containing compound 14 is obtained and it is used for the next step without further purification. Compound 15. Compound 14 (534 mg,) is dissolved in 50 ml of MeOH. The mixture is placed at –78°C and NaBH4 (27 mg, 0.72 mmol, 0.75 eq) is added. The mixture is stirred at -78°C for 3 h. At the end of the reaction, NH4Cl is added and the reaction is warmed at room temperature. The solvent is dissolved in a minimum of water and the pH is adjusted to 2. The solution is finally purified by FPLC (C18, H2O / CH3CN, 0.1% TFA) to give compound 15 as a TFA salt (126 mg, 0.19 mmol) with a 14% yield over two steps.1H NMR (400 MHz, MeOD): δ 8.74 (m, 2H, Ha / a’), 7.94 (m, 2H, Hc / c’), 7.76 (m, 2H, Hd / d’), 7.51 (m, 2H, Hb / b’), 5.62 (s, 1H, H2 / 4), 5.60 (s, 1H, H2 / 4), 4.41 (s, 1H, H9), 3.88 (m, 1H, H11), 3.73 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 3.51(m, 1H, H6 / 8), 3.47 (m, 1H, H12 / 12’), 3.28 (m, 1H, H6 / 8), 3.20 (m, 1H, H6 / 8), 3.08 (m, 1H, H12 / 12’), 2.99 (m, 1H, H6 / 8), 2.30 (s, 3H, H10). 13C NMR (126 MHz, MeOD): δ 173.34, 170.31, 168.96, 168.92, 151.40, 151.29, 149.62, 149.11, 137.63, 137.59, 127.78, 127.19, 124.82, 124.73, 72.43, 66.31, 65.71, 62.61, 55.35, 52.45, 51.95, 51.88, 51.85, 50.83, 48.70, 41.91, 34.07. Electrospray ionization ESI / MS+: m / z (%) = calculated for C27H33N4O9 [M + H]+, 557.22. Found 557.24. Compound 16. Compound 15 (311 mg, 0.46 mmol, 1 eq.) is solubilized in a mixture of 8 ml of CH3CN and 3 ml of THF. NHS (80 mg, 0.70 mmol, 1.5 eq) and DCC (229 mg, 1.11 mmol, 2.4 eq) are added to the solution. The mixture is stirred at room temperature for 2h. The formation of a solid is observed. The reaction is followed by TLC (9 / 1 DCM / MeOH). Once the reaction is completed, ethylenediamine (12 µL, 0.19 mmol, 0.4 eq) then DIPEA (95 µL, 0.56 mmol, 1.2 eq) are added to the solution. The reaction is stirred at room temperature for 2 days. The mixture is filtered and the solvent is evaporated. CH3CN (10 ml) is added to the solid, and the mixture is filtered. The filtrate is evaporated and the mixture is purified by FPLC (C18, 100% H2O, 0.1% TFA to 100% ACN, 0.1% TFA in 30 min) to give compound 16 as a TFA salt (120 mg). 1H NMR (500 MHz, MeOD): δ 8.88 (m, 2H, Ha), 8.78 (m, 2H, Ha’), 7.94 (m, 4H, Hc / c’), 7.75 (m, 4H, Hd / d’), 7.50 (m, 4H, Hb / b’), 5.63 (s, 2H, H2 / 4), 5.60 (s, 2H, H2 / 4), 4.39 (s, 2H, H9), 3.93 (m, 2H, H11), 3.72 (s, 6H, OMe), 3.70 (s, 3H, OMe), 3.68 (s, 3H, OMe), 3.48 (m, 2H, H6 / 8), 3.37 (m, 4H, H12 / 12’ + H13 / 13’), 3.21 (m, 2H, H6 / 8), 3.13 (m, 2H, H6 / 8), 2.96 (m, 4H, H6 / 8 + H12 / 12’), 2.32 (s, 6H, H10). 13C NMR (126 MHz, MeOD): δ 171.80, 171.78, 170.47, 170.42, 168.91, 151.37, 151.26, 149.69, 149.38, 137.70, 137.62, 127.63, 127.17, 124.80, 124.73, 72.33, 66.18, 65.59, 63.14, 55.08, 52.44, 51.95, 51.89, 50.82, 49.21, 42.01, 38.77, 35.70. MALDI-TOF: m / z (%) = calculated for C H N O , 11 + 56 68 10 16 36.48 [M+H] Found 1136.18. HPLC (C18Aq interchim 20 cm, from 95 / 5 H2O / ACN, 0.1% TFA to 100 CH3CN, 0.1% TFA in 15 min.) R.T. = 12.17 min l h i f i di d Compound 17. Potassium carbonate (123 mg, 0.89 mmol, 8 eq) is added to a solution of compound 15 (300 mg 0.45 mmol 4 eq) in 5 ml of CH3CN. The mixture is stirred for 30 min at 80 °C and a white precipitate is observed. The temperature is lowered to 50°C and 500 µl of water is added. After dissolution of the precipitate, HATU (510 mg, 1.34 mmol, 12 eq) is added. After 5 min, compound tris(2-aminoethyl)amine (16 mg, 0.11 mmol, 1 eq) is added to the mixture and the reaction is stirred at 50°C for 16 h. The reaction is monitored by HPLC. HATU is added (170 mg, 0.45 mmol, 4 eq). After 2 days, the solvent is removed under vacuum and the crude product is purified by FPLC (C18, H2O / CH3CN, 0.1% TFA) to give compound 17. SCHEME 10 Compound 18. Potassium carbonate (309 mg, 2.25 mmol, 15 eq) is added to a solution of compound 15 (500 mg 0.74 mmol 5 eq) in 7 ml of CH3CN. The mixture is stirred for 30 min at 80°C and a white precipitate is observed. The temperature is lowered to 50°C and 2.5 ml of water is added. After dissolution of the precipitate, HATU (850 mg, 2.27 mmol, 15 eq) is added. After 5 min, 2,2-bis(aminomethyl)propane-1,3-diamine (31 mg (63%), 0.15 mmol,1 eq) is added to the mixture and the reaction is stirred at 50°C for 16 h. The reaction is monitored by HPLC. HATU is added (283 mg, 0.74 mmol, 1 eq). After 2 days the solvent is removed under vacuum and the crude product is purified by FPLC (C18, H2O / CH3CN, 0.1% TFA) to give compound 18. Example 12: synthesis of other complexes of manganese (II) [(I-C), (I- D), (I-E), (I-F)] with bispidine-based metal chelating ligands (I-c), (I-g), (I- j), (I-h) respectively A complex (I-C) of manganese (II) with chelating bispidine-based ligand (I-c) of example 4 was prepared as follows: Compound (I-c) (30 mg, 2.41x10-5mol, 1 eq.) was suspended in 8 ml of H2O. pH was adjusted at 7 with a solution of HCl and KOH at 1 M and 0.1 M. 530 µL of a solution of MnCl2 at 0.1 M in H2O were added (2.2 eq). The pH was adjusted at 7. The solution was stirred at 60 °C overnight. The formation of the complex (I-C) was checked by HPLC. The solvent was evaporated, and the compound was purified by preparative HPLC to afford 17 mg of a white powder (yield: 51%). HPLC (C18Aq Interchim 20 cm, from 0 to 5 min: 100% H2O, from 5 to 7 min, 100% to 55 / 45 H2O / ACN, from 7 to 20 min, 55 / 45 H2O / ACN, from 20 to 22 min 100% ACN) RT = 12.1 min. A complex (I-D) of manganese (II) with chelating bispidine-based ligand (I-g) of example 5 was prepared as follows: Compound (I-g) (11 mg, 0.0044 mmol, 1 eq) is dissolved in 1 ml of water, and the pH is adjusted with LiOH 1 M to 7.5. A solution stock of MnCl2 was prepared by dissolving MnCl2 (42.5 mg, 0.34 mmol) in 5.076 g of a pH 4 solution buffer. Then, 269 µl (0.018 mmol, 4 eq) of this solution is added to the solution of compound (I-g) and the mixture is stirred at 60 °C for 1 hour. The reaction is monitored by HPLC (C18, H2O / ACN, 0.1% TFA). At the end, the mixture is purified by HPLC-prep (C18, H2O / ACN, 0.1% TFA). The pure fractions are gathered, and the pH is increased at 5-6 with 1 M LiOH the solution is oncentrated under vacuum and is purified a second time by HPLC-prep (C18, H2O / MeOH) to finally give Mn3(I-g) (i.e. compound (I-D)) (7 mg) with 85% ield. Electrospray ionization ESI / HRMS+: m / z (%) = calculated for C84H100Mn3N16O24 [M3++ H+]4+470.6312 C84H99Mn3N16O24 [M]3+626.8381, C84H98Mn3N16O24, [M3+-H+]2+939.7535, C86H99Mn3N16O26F3 997.2531 [M3++ CF3COO-]2+. Found 470.6324, 626.8388, 939.7541, 997.2520. HPLC (C18Aq Interchim 20 cm, de 95 / 5 H2O / ACN, 0.1 % TFA to 100 ACN 0.1% TFA in 15 min) RT = 9.38 min. A complex (I-E) of manganese (II) with chelating bispidine-based ligand I-j) of example 8 was prepared as follows: Compound (I-j) (34 mg, 0.015 mmol, 1 eq) is dissolved in 2.4 ml of water, and the pH is adjusted with 1 M LiOH to 7.5. A stock solution of MnCl2 was prepared by dissolving MnCl2 (73 mg, 0.58 mmol) in 5.424 g of a pH 4 solution buffer (citric acid / HCl). Then, 534 µl (0.057 mmol, 3.8 eq) of this solution is added to the solution f compound (I-j) and the mixture is stirred at 60 °C for 1 hour. The reactions monitored by HPLC (C18, H2O / ACN, 0.1% TFA). At the end, the mixture is purified by HPLC-prep (C18, H2O / ACN, 0.1% TFA). The pure fractions are gathered, and the pH is increased to pH 5-6 with a 1 M LiOH solution and the rude mixture is concentrated under vacuum. A second batch of complex is synthesized with 10 mg of compound (I-j) 0.004 mmol, 1 eq) and the two batches are gathered to be purified a second ime by HPLC-prep (C18, H2O / MeOH) to finally give Mn3(I-j) (compound (I-E)) 22 mg) with 76% yield (with the two batches). Electrospray ionization ESI / HRMS+: m / z (%) = calculated for C87H96Mn3N15O243+[M]3+633.4949, [M3+-H+]2+949.7434, C89H96F3Mn3N15O26 [M3++ CF3COO-]2+1006.7398. Found 633.4983, 949.7435, 1006.7397. Elemental Analysis: calculated for Mn3(C87H96N15O24)(Cl)3(H2O)3](LiCl)3(H2O)6, C, 45.10, H, 4.96, N, 9.18. Found: C, 45.51, H, 5.00, N, 9.26. HPLC (C18Aq Interchim 20 cm, from 95 / 5 H2O / ACN, 0.1% TFA to 100% ACN 0.1% TFA in 15 min.) RT = 9.46 min. A complex (I-F) of manganese (II) with chelating bispidine-based ligand (I-h) of example 7 was prepared as follows: Compound (I-h) (12 mg, 0.0040 mmol, 1 eq) is dissolved in 1 ml of water, and the pH of the solution is adjusted with LiOH 1 M to 7.5. A stock solution of MnCl2 was prepared by dissolving MnCl2 (15.3 mg, 0.122 mmol) in 1 g of a pH 4 citrate / HCl buffer solution. Then, 167 µl (0.02 mmol, 5 eq) of this solution is added to the solution of compound (I-h) and the mixture is stirred at 60°C for 1 hour. The reactions monitored by HPLC (C18, H2O / CH3CN, 0.1 % TFA). At the end of the reaction, the mixture is purified by preparative HPLC on reverse phase column (C18, H2O / CH3CN, 0.1% TFA). The pure fractions are gathered, and the pH is increased to pH 5-6 with a 1 M LiOH solution. The solution is concentrated to dryness under vacuum and the resulting product is further purified by running a second preparative HPLC purification (C18, H2O / MeOH) to finally give Mn4(I-h) (I-F) (2.3 mg, 0.91 mmol) with 18% yield. Electrospray ionization ESI / MS+: m / z (%) = calculated for C114H132Mn4N22O32, 2541.70 [M+H]+, 2655.69 [M+H+CF3COOH]+Found 2541.70, 2655.68. HPLC (C18Aq Interchim 20 cm, from 95 / 5 H2O / CH3CN, 0.1% TFA to 100 CH3CN 0.1% TFA in 15 min) R.T. = 9.62 min. Table 2 below shows the properties of complexes (I-C), (I-D), (I-E) and (I-F). Longitudinal relaxivity r1,Mn is expressed per millimolar concentration of Mn(II). As a reminder the relaxivity of complex (I-A) is reported. Example 13: kinetic inertness of the bispidine-Mn(II) complex (I-D) The kinetic inertness of the complex (I-D) has been evaluated in human plasma (1 µM) at 37°C, using HPLC-MS. No dissociation of the complex (I-D) was observed within a time frame of 48h. The dissociation of the complex (I-D) has also been evaluated via a transmetallation reaction in the presence of 50 equiv. of Zn2+at pH = 6 (50 mM MES buffer) at 37°C, over a period of 140 days. Within this timeframe, limited relaxivity changes were observed, corresponding to ~15% dissociation as demonstrated in figure 2 which indicates the dissociation half-live, t1 / 2.in s-1as a function of time (in days). Under similar conditions (37°C, pH 6.0, 25 Zn2+equivalents), dissociation half-lives, t1 / 2, of 0.285 h and 54.4 h have been reported respectively for MnPyC3A (E. M. Gale, I. P. Atanasova, F. Blasi, I. Ay, P. Caravan, J. Am. Chem. Soc. 2015, 137, 15548-15557) and MnPC2A-EA (Botár, R.; Molnár, E.; Trencsényi, G.; Kiss, J.; Kálmán, F. K.; Tircsó, G. J. Am. Chem. Soc. 2020, 142, 1662), two reference compounds considered as potential MRI probes with good kinetic inertness. Example 14: in vitro evaluation of the bispidine-Mn(II) complexes (I-D) and (I-E) on phantoms 9.4T MRI images (Biospin, Bruker, Wissembourg, France) of phantoms with solutions of complexes (I-D) and (I-E) in water and in mice serum have been measured. Relaxation times have been measured with a spin echo sequence (matrix = 256*256, FOV = 33 cm, slice thickness = 1 mm, TE / TR = 10, 30, 50, 70, 90 / 200, 600, 1000, 2000, 3000 ms, 10 min).and determined with Paravision PV5.1. Signal intensity has been measured with a T1-weighted RARE sequence (matrix = 256*256, FOV = 33 cm, slice thickness = 1 mm, TE / TR = 21 / 400 ms). Figure 3 represents Ti-weighted 9.4T MRI images of phantom solutions of (I-D) and (I-E) complexes in water and in mice serum on an 9.4T MRI scanner (Biospin, Bruker, RARE sequence). Images of figure 3 indicate the samples concentration in mM. Dotarem® has been used for comparison.

[0266] A significant signal enhancement is observed in the presence of (I-D) and (I-E) complexes. The measured longitudinal relaxivity (n) for (I-E) in water (4.39 9.4T) is higher than that of the reference complex

[0267] Dotarem® (4.32 mM^s^ at 0.75 mM and 4.12 mM^s^ at 1.5 mM).

[0268] Example 15: in vivo evaluation of the bispidine-Mn(II) complexes (I-D) and (I-E) on wild type mice

[0269] MRI studies were conducted on BalbC mice (n=5 for each complex) following ethical guidelines set by the Ministry of Agriculture (Project Authorization No. 20366). General anaesthesia was induced using 2.5% isoflurane and an oxygen / air mixture (1 : 1) at 0.5 l / min. The contrast agent was delivered to the mouse via a long catheter inserted into the caudal vein. The catheter was sufficiently long to extend outside the imaging device to avoid disturbing the animal during the entire acquisition period. During the experiments, mice were placed on a custom cradle to immobilize the head. They were anaesthetized with 1.5% isoflurane and an oxygen / air mixture (1 : 1) at a flow rate of 0.5 l / min. Respiratory monitoring was conducted throughout the protocol using a motion sensor placed under the animal's rib cage. Body temperature was maintained at 37°C using a heating pad.

[0270] The complexes were diluted in PBS (15 mM in 10 mM PBS / pH=7.4 and 7.5 mM in 10 mM PBS / pH=7.2, for (I-D) and (I-E) complexes, respectively. The injected dose was 60 pmol / kg.

[0271] To validate the potential in vivo use of (I-D) and (I-E) complexes, there biodistribution in wild-type mice using MRI at 9.4 T was evaluated. The signal intensity was monitored in the main organs (kidney, liver, lung, medulla, cortex, renal and lung artery) over 24h post-intravenous injection (0.06 mmol / kg dose). Figure 4 represents the average normalized signal intensity for the analysed organs as a function of time for five mice post-intravenous injection (0.06 mmol / kg dose) of (I-D) (top) and (I-E) (bottom). Images have been recorded using a spin-echo sequence (RAR.E4 TE / TR=21 / 250 ms, matrix=128*12S / FOV=63 cm, slice thickness=70 pm). Standard deviations are not presented for better readability.

[0272] (I-D) and (I-E) complexes exhibit a biodistribution comparable to that observed for conventional gadolinium-based agents in clinical use, with renal elimination and excretion via the bladder and limited uptake in the liver. The highest intensity signal was reached 2 minutes after injection of the complex. After 10 minutes, the signal intensity in the blood decreases by 50%.

[0273] Example 16: ex vivo biodistribution of the bispidine-Mn(II) complexes and (I-E) on wild type mice

[0274] Complete elimination of the probes from the mice was confirmed by an ex vivo biodistribution study. Mice were sacrificed at 24 h post injection (0.06 mmol / kg dose) and the organs harvested. The manganese content was determined by ICP-MS in different organs following acid digestion. Figure 5 represents the Mn content in nmol / g as a function of the organ. Ex vivo ICP- OES was used to quantify the Mn tissue content in the major organs and blood of mice, both control and injected with (I-D) and (I-E) complexes (24 hours post-injection). Data are presented as nmol / g tissue ± SD (n = 5).

[0275] The ICP-OES measurements were performed with a Jobin Yvon ULTIMA2 Spectrometer (Longjumeau, France). Standard Mn solutions were prepared from a commercial Multielement solution 1 for ICP (Sigma-Aldrich, France) in 5% HNO3 matrix. The samples were digested in cone HNO3 for 48 h at room temperature followed by 18 h at 65°C. The resulting solutions were then diluted 1 : 12, to reach 5% in HNO3. Measurements were performed in triplicate, using the most accurate band for Mn (257.610 nm) yielding a calibration curve with R2of 0.9997. Data are presented as mean±SD (n=5).

[0276] The results obtained are compared with baseline values obtained for control mice that did not receive Mn(II) injection.

[0277] The studies confirm that (I-D) and (I-D)complexes are completely excreted from the body 24 h after injection. Table 3 represents Mn(II) tissue content of endogenous (baseline) and following 24h injection of 0.06 mmol / kg of MnL in wild type mice (C57BL / 6JRj) determined by ICP-OES. Data are presented as nmol / g ± SD (n = 5).

Claims

CLAIMS 1. A bispidine-based metal chelating ligand responding to the following formula (I): L-(R)n (I) wherein n represents an integer such as n ≥ 2, and R groups represent, independently from each other, ^ a group R1-(T1)r-CH2*-, in which T1represents a C1-C10 alkylene group, and r represents an integer 0 or 1, and / or ^ a group responding to the following formula (II): in which:- T2represents a C1-C10 alkylene group, - A represents -CH2- or -NH-, - X represents an oxygen atom, a sulfur atom, or a NH group, -s represents an integer 0 or 1 when A represents -CH2- and s represents an integer 1 when A represents -NH-; and wherein * indicates the point of attachment of said group R with L, wherein R1is a bispidol group of the following formula (III): in which:- R2represents a PO3H2 group or a CO2H group, - R3and R4, which may be identical or different, represent a CO2H group or a CH2OH group, - R5represents a hydrogen atom, an alkyl group, or a group of formula (IV): –T3-CO2H (IV) where T3represents a C1-C5 alkylene group, - R6, R7, R8, R9, R10, R11, R12, and R13, independently from each other, represent a hydrogen atom, an OH group, an ether group OR14where R14is an alkyl group, a CO2H group, or a CONHR15group, where R15represents an alkyl group, - when r, respectively s, represents an integer 1, * indicates the point of attachment of said group R1with T1, respectively with T2, and when r, respectively s, represents an integer 0, * indicates the point of attachment of said group R1with -CH2-, respectively with -A-, wherein L is at least a divalent linker selected from: ● a single bond, ● a guanidine group, ● an urea group, ● a thiourea group, ● a C5-C18 aryl group, ● a C2-C18 heteroaryl group, ● a C2-C10 alkyl group, ● a group responding to formula (V): *NH-D(NH*)t-NH* (V) in which D is selected from an aryl group, an heteroaryl group, an alkyl group, a 3-cyclobutene-1,2-dione group, a polyethylene group, and a polyaminoacid group, and t is an integer ranging from 0 to 6, ^ a group responding to the following formula (VI): *NH-(CR16R17)m1-[NR20-(CR18R19)q1]p1-NH* (VI) in which:- R16and R17represent, independently from each other, independently at each occurrence m1, a hydrogen atom or a C1-C5 alkyl group, - m1 is an integer ranging from 2 to 5, - R18and R19represent, independently from each other, independently at each occurrence q1, independently at each occurrence p1, a hydrogen atom or a C1-C5 alkyl group, - R20represents, independently at each occurrence p1, a hydrogen atom, a C1-C5 alkyl group, a group -T4-NH*- in which T4represents a C2-C5 alkylene group, or a single bond*, - q1 represents, independently at each occurrence p1, an integer ranging from 2 to 5, and - p1 is an integer ranging from 0 to 4, ^ a group responding to the following formula (VII): *E-NH-(CR16R17)m1-[NR21-(CR18R19)q1]p1-NH-E* (VII) in which: - R16, R17, R18, and R19are as defined above, - m1, q1, and p1 are as defined above, - R21represents, independently at each occurrence p1, a hydrogen atom, a C1-C5 alkyl group, a group -T5-NH-E* in which T5represents a C2-C5 alkylene group, or a single bond*, - E is a 3-amino-, or 4-amino-3-cyclobutene-1,2-dione group, or a C1-C5 alkyl group, ^ a group responding to the following formula (VIII): *(CR22R23)m2-NR28-[(CR24R25)q2-NR29]p2-(CR26R27)m3* (VIII) in which: - R22and R23represent, independently from each other, independently at each occurrence m2, a hydrogen atom or a C1-C5 alkyl group, - m2 is an integer ranging from 1 to 5,- R24and R25represent, independently from each other, independently at each occurrence q2, independently at each occurrence p2, a hydrogen atom or a C1-C5 alkyl group, - R26and R27represent, independently from each other, independently at each occurrence m3, a hydrogen atom or a C1-C5 alkyl group, - m3 is an integer ranging from 1 to 5, - R28represents a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*, - R29represents, independently at each occurrence p2, a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, a single bond*, or a -[(CR24R25)q2- NR29]p2-(CR26R27)m3* group, - q2 represents, independently at each occurrence p2, an integer ranging from 2 to 5; and - p2 is an integer ranging from 0 to 4, ^ a group responding to the following formula (IX): *(CR30R31)m4-NR34-[(CH2-CH2-O)q4-CH2-CH2-NR35]p4-(CR32R33)m5* (IX) in which: - R30and R31represent, independently from each other, independently at each occurrence m4, a hydrogen atom or a C1-C5 alkyl group, - m4 is an integer ranging from 1 to 5, - R32and R33represent, independently from each other, independently at each occurrence m5, a hydrogen atom or a C1-C5 alkyl group, - m5 is an integer ranging from 1 to 5, - R34represents a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*, - R35represents, independently at each occurrence p4, a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*, - q4 represents, independently at each occurrence p4, an integer ranging from 1 to 5, and - p4 is an integer ranging from 0 to 4,wherein * in formulae (V) to (IX) indicates the possible points of attachment of said linker L with groups R,• a polyazacycloalkane saturated group in which at least two -N- functions represent points of attachment of said linker L with groups R,• a polyaminoacid group in which at least two functions represent points of attachment of said linker L with groups R, said function being a carbonyl function (derived from the carboxylic acid function), a thiol function, or an amine function,• a polyamidoamine group in which at least two -NH- functions represent points of attachment of said linker L with groups R.

2. The ligand according to claim 1, wherein at least two R groups represent a group R1-T1-CH2*-, in which T1represents a C1-C4 alkylene group.

3. The ligand according to claim 1 or claim 2, wherein at least two R groups represent a group responding to said following formula (II), where A represents -NH-, and X represents an oxygen atom, a sulfur atom, or a NH group, or A represents -CH2- and X represents an oxygen atom.

4. The ligand according to any one of the preceding claims, wherein R3and R4represent CO2H groups.

5. The ligand according to any one of the preceding claims, wherein R2represents a CO2H group.

6. The ligand according to any one of the preceding claims, wherein L is a polyazacycloalkane saturated group selected from cyclen, cyclam, and derivatives thereof.

7. The ligand according to any one of the preceding claims, wherein R5is a linear C1-C5 alkyl group.

8. The ligand according to any one of the preceding claims, wherein at least R7and R11, and / or R9and R13represent hydrogen atoms, and preferably R6, R7, R8, R9, R10, R11, R12, and R13groups represent hydrogen atoms.

9. The ligand according to any one of the preceding claims, wherein L responds to any one of the following formula (V):wherein * represent the possible points of attachment of the linker L to the group R.

10. The ligand according to any one of the preceding claims, wherein L responds to the any one of the following formula (VI) :wherein * represent the possible points of attachment of the linker L to the group R.

11. The ligand according to any one of the preceding claims, wherein L responds to the following formula (VII):wherein * represent the possible points of attachment of said linker L to the group R.

12. The ligand according to any one of the preceding claims, wherein L responds to any one the following formula (VIII):wherein * represent the possible points of attachment of the linker L to the group R..

13. The ligand according to any one of the preceding claims, wherein said ligand is selected from the following formulae (I-a) to (I-n) and salts thereof:

14. A complex of a metal M, wherein said complex comprises several metal ions of said metal M complexed with a bispidine-based metal chelating ligand (I) as defined in any one of the preceding claims, said metal M being selected from copper, manganese, gallium, cobalt, zinc, nickel, and iron.

15. A bispidine-based metal chelating ligand (I) as defined in any one of claims 1 to 13, or of a complex as defined in claim 14, for use in the field of medical imaging or therapy, and more specifically as MRI contrast agents and / or nuclear imaging agents for PET or SPECT.

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