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EP-4739689-A1 - NOVEL BISPIDINE-BASED METAL CHELATING LIGANDS DISPLAYING GOOD RELAXIVITY

EP4739689A1EP 4739689 A1EP4739689 A1EP 4739689A1EP-4739689-A1

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).

Inventors

  • NONAT, ALINE
  • CHARBONNIERE, Loïc
  • SY, Maryame
  • CHARPENTIER, Cyrille
  • Jakab Tóth, Eva

Assignees

  • Université de Strasbourg
  • Centre National de la Recherche Scientifique

Dates

Publication Date
20260513
Application Date
20240703

Claims (15)

  1. 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 R 1 -(T 1 )r-CH2*-, in which T 1 represents 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: - T 2 represents 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 R 1 is a bispidol group of the following formula (III): in which: - R 2 represents a PO3H2 group or a CO2H group, - R 3 and R 4 , which may be identical or different, represent a CO2H group or a CH2OH group, - R 5 represents a hydrogen atom, an alkyl group, or a group of formula (IV): –T 3 -CO2H (IV) where T 3 represents a C1-C5 alkylene group, - R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 , independently from each other, represent a hydrogen atom, an OH group, an ether group OR 14 where R 14 is an alkyl group, a CO2H group, or a CONHR 15 group, where R 15 represents an alkyl group, - when r, respectively s, represents an integer 1, * indicates the point of attachment of said group R 1 with T 1 , respectively with T 2 , and when r, respectively s, represents an integer 0, * indicates the point of attachment of said group R 1 with -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-(CR 16 R 17 )m1-[NR 20 -(CR 18 R 19 )q1]p1-NH* (VI) in which: - R 16 and R 17 represent, 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, - R 18 and R 19 represent, independently from each other, independently at each occurrence q1, independently at each occurrence p1, a hydrogen atom or a C1-C5 alkyl group, - R 20 represents, independently at each occurrence p1, a hydrogen atom, a C1-C5 alkyl group, a group -T 4 -NH*- in which T 4 represents 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-(CR 16 R 17 )m1-[NR 21 -(CR 18 R 19 )q1]p1-NH-E* (VII) in which: - R 16 , R 17 , R 18 , and R 19 are as defined above, - m1, q1, and p1 are as defined above, - R 21 represents, independently at each occurrence p1, a hydrogen atom, a C1-C5 alkyl group, a group -T 5 -NH-E* in which T 5 represents 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): *(CR 22 R 23 )m2-NR 28 -[(CR 24 R 25 )q2-NR 29 ]p2-(CR 26 R 27 )m3* (VIII) in which: - R 22 and R 23 represent, 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, - R 24 and R 25 represent, independently from each other, independently at each occurrence q2, independently at each occurrence p2, a hydrogen atom or a C1-C5 alkyl group, - R 26 and R 27 represent, 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, - R 28 represents a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*, - R 29 represents, independently at each occurrence p2, a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, a single bond*, or a -[(CR 24 R 25 )q2- NR 29 ]p2-(CR 26 R 27 )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): *(CR 30 R 31 )m4-NR 34 -[(CH2-CH2-O)q4-CH2-CH2-NR 35 ]p4-(CR 32 R 33 )m5* (IX) in which: - R 30 and R 31 represent, 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, - R 32 and R 33 represent, 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, - R 34 represents a hydrogen atom, a C1-C5 alkyl group, a C1-C5 alkylene group*, or a single bond*, - R 35 represents, 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. 2. The ligand according to claim 1, wherein at least two R groups represent a group R 1 -T 1 -CH2*-, in which T 1 represents a C1-C4 alkylene group.
  3. 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. 4. The ligand according to any one of the preceding claims, wherein R 3 and R 4 represent CO2H groups.
  5. 5. The ligand according to any one of the preceding claims, wherein R 2 represents a CO2H group.
  6. 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. 7. The ligand according to any one of the preceding claims, wherein R 5 is a linear C1-C5 alkyl group.
  8. 8. The ligand according to any one of the preceding claims, wherein at least R 7 and R 11 , and/or R 9 and R 13 represent hydrogen atoms, and preferably R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 groups represent hydrogen atoms.
  9. 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. 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. 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. 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. 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. 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. 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.

Description

NOVEL BISPIDINE-BASED METAL CHELATING LIGANDS DISPLAYING GOOD RELAXIVITY 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). 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®). 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. 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. 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. 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. 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'1 at pH of 7.4, 60 MHz, and 25°C. 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. 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 and 52Mn-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'1 at pH of 7.