New astatoaryl compounds and their use

Abstract

The inventors have now succeeded in developing new astatoaryl compounds, as well as a method for synthesizing said astatoaryl compounds comprising the step of reacting aryl compounds carrying a leaving group with astatine. These astatoaryl compounds have the advantage of having one hydrogen bond donor in the At environment which improves stability against oxidative deastatination and a second hydrogen bond donor which further improves this stability. In particular, benzylic alcohol functions in ortho position to At successfully leads to improved stability compared to the gold standard astatobenzoate in KMnO4 solution or human and rat microsomes. The present invention relates to astatoaryl compounds, a method for synthesizing astatoaryl compounds comprising the reaction of an aryl compound carrying a leaving group with astatine. The invention also concerns a method of synthesizing an astatolabelled biomolecule and / or vector using said astatoraryl compound.

Description

[0001] NEW ASTATOARYL COMPOUNDS AND THEIR USE

[0002] The present invention relates to astatoaryl compounds, a method for synthesizing astatoaryl compounds comprising the reaction of an aryl compound carrying a leaving group with astatine. The invention also concerns a method of synthesizing an astatolabelled biomolecule and / or vector using said astatoraryl compound.

[0003] BACKGROUND OF THE INVENTION

[0004] With its intermediate half-life (7.2 h) and short track / high energy a particles emitted upon decay,211At appears as one of the most promising radionuclides for targeted alpha therapy of cancers (Eychenne, R. et aL, Pharmaceutics 2021, 13, 906). A number of molecules have been labelled, from small compounds to peptides and proteins (Eychenne, R. et al., in Nuclear Medicine and Molecular Imaging, Elsevier, 2022, p. 121-132) using as main approach the grafting of an astatoaryl prosthetic group. While this approach seems sufficiently stable to keep211At attached to its vector when it is applied to intact and noninternalizing monoclonal antibodies, it appears less stable for the labeling of smaller molecules or proteins internalized within targeted cells (Wilbur, S. D., Curr. Radiopharm. 2008, 1, 144-176; Guerard, F. et al., Acc. Chem. Res. 2021, 54, 3264-3275). Several hypotheses were developed to explain the in vivo degradation of the carbon-astatine bond which appears significantly accelerated compared to the closely related carbon-iodine bond. On the one hand, oxidizing and acidic conditions found in the lysosomes in the cell nucleus were attributed to this bond breakage (Teze, D. et al., Sci. Rep. 2017, 7, 2579). On the other hand, it was proposed that selenocysteine mediated dehalogenation could also be a reasonable explanation for this in vivo instability (Yssartier, T. et al. , RSC Med. Chem. 2024, 15, 223-233).

[0005] There is thus a need for new radioastatoaryl compounds having improved stability.

[0006] SUMMARY OF THE INVENTION

[0007] The inventors have now succeeded in developing new astatoaryl compounds, as well as a method for synthesizing said astatoaryl compounds comprising the step of reacting aryl compounds carrying a leaving group with astatine. These astatoaryl compounds have the advantage of having one hydrogen bond donor in the At environment which improves stability against oxidative deastatination and a second hydrogen bond donor which further improves this stability. In particular, benzylic alcohol functions in ortho position to At successfully leads to improved stability compared to the gold standard astatobenzoate in KMnO4 solution or human and rat microsomes.

[0008] In a general aspect, the invention provides an astatoaryl compound of formula (I): wherein R1is selected from H, hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl, and wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl;

[0009] R2is selected from hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl and wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl; and

[0010]

[0011] The invention also relates to a compound of Formula (II):

[0012] (II), wherein

[0013] R1is selected from H, hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl and wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl;

[0014] R2is selected from hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl and wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl;

[0015] Y is a monovalent anion;

[0016] M is Si or Sn;

[0017] R7is Cl-C6-alkyl;

[0018] R8is selected from H, Cl-C6-alkyl and Cl-C6-alkoxy;

[0019] R9and R10are independently selected from H, Cl-C6-alkyl and Cl-C6-alkoxy; and represents a single bond or is inexistent. The present invention also relates to a method for synthesizing an astatoaryl compound of Formula (I) comprising the step of reacting an aryl compound carrying a leaving group with astatine.

[0020] The present invention also relates to method of synthesizing an astatolabelled biomolecule and / or vector comprising the steps of:

[0021] (i) synthesizing astatoaryl compound of Formula (I) according to the method for synthesizing an astatoaryl compound of Formula (I) of the invention; and

[0022] (ii) reacting said astatoaryl compound with a biomolecule and / or a vector carrying a functional group reactive with said iodo- or astatoaryl compound. DETAILED DESCRIPTION OF THE INVENTION

[0023] Astatoaryl compound

[0024] As detailed above, the invention relates to an astatoaryl compound of formula (I):

[0025] (I), wherein

[0026] R1is selected from H, hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl, and wherein R5is hydroxy-C 1 -C2-alkyl and R6is H or hydroxy-C 1 -C2-alkyl; in particular R1is selected from H, hydroxy-C l-C2-alkyl, C(O)NHR4wherein R4is C1-C2- alkyl, and wherein R5is hydroxymethyl or OH and R6is H or hydroxymethyl; more particularly R1is selected from H, hydroxy-C l-C2-alkyl and C(O)NHR4wherein R4is Cl-C2-alkyl; still more particularly R1is H or hydroxy-C 1-C2- alkyl; even more particularly R1is H or hydroxymethyl; R2is selected from hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl and wherein R5is hydroxy-C 1 -C2-alkyl and R6is H or hydroxy-C 1 -C2-alkyl; in particular R2is selected from hydroxy-C l-C2-alkyl, C(O)NHR4wherein R4is Cl-C2-alkyl, wherein R5is hydroxymethyl or OH and R6is H or hydroxymethyl; more particularly R2is hydroxy-C l-C2-alkyl or C(O)NHR4wherein R4is Cl-C2-alkyl; still more particularly R2is hydroxy-C l-C2-alkyl; even more particularly R2is hydroxymethyl; and

[0027]

[0028] The symbol used herein means that R3may be located as any free position of the phenyl ring.

[0029] In one embodiment, the compounds of Formula I are those wherein R1is hydroxy-Cl-C2- alkyl, R2is hydroxy-Cl-C2-alkyl and R3is H.

[0030] In one embodiment, the compounds of Formula I are those wherein R1is H, R2is hydroxy - Cl-C2-alkyl and R3is H. In one embodiment, the compounds of Formula I are those wherein R1is hydroxy-Cl-C2- alkyl, R2is hydroxy-Cl-C2-alkyl and R3is selected from -N=C=S, -CH2-N3,

[0031]

[0032] 5 In one embodiment, the compounds of Formula I are those wherein R1is H, R2is hydroxy- particular R3is selected from

[0033] In one embodiment, the compounds of Formula I are those wherein R1and R2are C(O)NHR4wherein R4is Cl-C4-alkyl, in particular R4is Cl-C2-alkyl, more particularly R4is methyl, and R3is H.

[0034] In one embodiment, the compounds of Formula I are those wherein R1is H, R2is C(O)NHR4wherein R4is Cl-C4-alkyl, in particular R4is Cl-C2-alkyl, more particularly R4is methyl, and R3is H. In one embodiment, the compounds of Formula I are those wherein R1and R2are C(O)NHR4wherein R4is Cl-C4-alkyl, in particular R4is Cl-C2-alkyl, more particularly R4is methyl, and R3is selected from -N=C=S, -CH2-N3,

[0035]

[0036] 5 In one embodiment, the compounds of Formula I are those wherein R1is H, R2is C(O)NHR4wherein R4is Cl-C4-alkyl, in particular R4is Cl-C2-alkyl, more particularly R4is methyl,

[0037]

[0038] In one embodiment, the compounds of Formula I are those wherein R4is methyl. In one embodiment, the compounds of Formula I are those wherein wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, R2is wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, and R3is H. In one embodiment, the compounds of Formula I are those wherein R1is H, R2is wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, and R3is H.

[0039] In one embodiment, the compounds of Formula I are those wherein wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, R2is wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, particular R3is selected from

[0040]

[0041] In one embodiment, the compounds of Formula I are those wherein R1is H, R2is wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, particular R3is selected from

[0042] In one embodiment, particular astatoaryl compounds of the invention are those of Formula (I-a):

[0043] (I-a), wherein R1and R2are as defined in Formula (I).

[0044] Particular compounds of Formula (I-a) are those wherein one or more of R1and R2are defined as follows:

[0045] R1is H or hydroxy-Cl-C2-alkyl; in particular R1is H or hydroxymethyl; and

[0046] R2is hydroxy-Cl-C2-alkyl; in particular R2is hydroxymethyl.

[0047] In one embodiment, the compounds of Formula (I-a) are those wherein R1is H and R2is hydroxy-Cl-C2-alkyl, in particular R2is hydroxymethyl.

[0048] In one emdodiment, the compounds of Formula (I-a) are those wherein R1and R2are hydroxy-Cl-C2-alkyl, in particular R1and R2are hydroxymethyl. In one embodiment, particular astatoaryl compounds of the invention are those of Formula

[0049] (I-b):

[0050] (I-b), wherein R1, R2and R3are as defined in Formula (I).

[0051] Particular compounds of Formula (I-b) are those wherein one or more of R1, R2and R3are defined as follows:

[0052] R1is H or hydroxy-Cl-C2-alkyl; in particular R1is H or hydroxymethyl;

[0053] R2is hydroxy-Cl-C2-alkyl; R2is hydroxymethyl; particular R3is H.

[0054] In one embodiment, the astatoaryl compound of the invention is represented by the Formula

[0055] (I-c): wherein R1, R2and R3are as defined in Formula (I).

[0056] Particular compounds of Formula (I-c) are those wherein one or more of R1, R2and R3are defined as follows:

[0057] R1is H or hydroxy-Cl-C2-alkyl; in particular R1is H or hydroxymethyl; R2is hydroxy-Cl-C2-alkyl; R2is hydroxymethyl; and

[0058] In one embodiment, particular astatoaryl compounds of the invention are those of Formula (I-d):

[0059] (I-d), wherein R1, R2and R3are as defined in Formula (I).

[0060] In one embodiment, particular astatoaryl compounds of the invention are those of Formula (I-e):

[0061] (I-e), wherein R1and R2are as defined in Formula (I).

[0062] Particular compounds of Formula (I-e) are those wherein one or more of R1and R2are defined as follows:

[0063] R1is H or hydroxy-Cl-C2-alkyl; in particular R1is H or hydroxymethyl;

[0064] R2is hydroxy-Cl-C2-alkyl; R2is hydroxymethyl.

[0065] In one embodiment, particular astatoaryl compounds of the invention are those of Formula (I-f):

[0066] (I-f), wherein R1and R2are as defined in Formula (I). In one embodiment, particular astatoaryl compounds of the invention are those of Formula (I-g): wherein R1and R2are as defined in Formula (I).

[0067] Particularly preferred astatoaryl compounds of Formula (I) are those listed in Table 1 hereafter:

[0068] Table 1

[0069]

[0070] Particular astatoaryl compounds of Formula (I) are Compounds 1-1 and 1-2.

[0071] The astatoaryl compounds of the invention can be prepared by different ways with reactions known by the person skilled in the art, in particular as described by the examples.

[0072] Aryl compound As detailed above, the invention relates to an aryl compound of formula (II):

[0073] (II), wherein

[0074] R1is selected from H, hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl, and wherein R5is hydroxy-C 1 -C2-alkyl and R6is H or hydroxy-C 1 -C2-alkyl; in particular R1is selected from H, hydroxy-C l-C2-alkyl, C(O)NHR4wherein R4is C1-C2- alkyl, and wherein R5is hydroxymethyl or OH and R6is H or hydroxymethyl; more particularly R1is selected from H, hydroxy-C l-C2-alkyl and C(O)NHR4wherein R4is Cl-C2-alkyl; still more particularly R1is H or hydroxy-C 1-C2- alkyl; even more particularly R1is H or hydroxymethyl; R2is selected from hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl and wherein R5is hydroxy-C 1 -C2-alkyl and R6is H or hydroxy-C 1 -C2-alkyl; in particular R2is selected from hydroxy-C l-C2-alkyl, C(O)NHR4wherein R4is Cl-C2-alkyl, wherein R5is hydroxymethyl or OH and R6is H or hydroxymethyl; more particularly R2is hydroxy-C l-C2-alkyl or C(O)NHR4wherein R4is Cl-C2-alkyl; still more particularly R2is hydroxy-C l-C2-alkyl; even more particularly R2is hydroxymethyl;

[0075] particular example LG is selected from

[0076]

[0077] Y is a monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; still more particularly Y is TsO;

[0078] M is Si or Sn; in particular M is Si;

[0079] R7is Cl-C6-alkyl;

[0080] R8is selected from H, Cl-C6-alkyl and Cl-C6-alkoxy; in particular R8is selected from H, Cl-C4-alkyl and Cl-C4-alkoxy; more particularly R8is selected from H,

[0081] Cl-C2-alkyl and Cl-C2-alkoxy; still more particularly R8is selected from H, methyl and methoxy;

[0082] R9and R10are independently selected from H, Cl-C6-alkyl and Cl-C6-alkoxy; in particular R9and R10are H or Cl-C6-alkoxy; more particularly R9and R10are independently H or Cl-C4-alkoxy; still more particularly R9and R10are independently H or Cl-C2-alkoxy; even more particularly R9and R10are H or methoxy; and represents a single bond or is inexistent. As used herein, the term “TfO” refers to the group trifluoromethane sulfonate, also named triflate, of the following formula: CF3SO3.

[0083] As used herein, the term “TsO” refers to the group para-toluenesulfonate, also named tosylate, of the following formula: CH3C6H4SO3.

[0084] As used herein, the term “MsO” refers to the group methanesulfonate, also named mesylate, of the following formula: CH3SO3.

[0085] In one embodiment, the compound of Formula II is as defined above with the proviso that

[0086] R3is not H when are hydroxymethyl.

[0087] In one embodiment, the compound of Formula II is as defined above with the proviso that

[0088] R3is not H when hydroxymethyl.

[0089] In one embodiment, the compounds of Formula II are those wherein LG is wherein Y is a monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; still more particularly Y is TsO.

[0090] In one embodiment, the compounds of Formula II are those wherein In one embodiment, the compounds of Formula II are those wherein LG is In one embodiment, the compounds of Formula II are those wherein LG is -M(R7)s wherein

[0091] M is Si or Sn and R7is Cl-C6-alkyl.

[0092] In one embodiment, the compounds of Formula II are those wherein LG is wherein Y is a monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; still more particularly Y is TsO; R8is selected from H, Cl-C6-alkyl and C1-C6- alkoxy; in particular R8is selected from H, Cl-C4-alkyl and Cl-C4-alkoxy; more particularly R8is selected from H, Cl-C2-alkyl and Cl-C2-alkoxy; still more particularly R8is selected from H, methyl and methoxy; R9and R10are independently selected from H, Cl-C6-alkyl and Cl-C6-alkoxy; R9and R10are independently selected from H, Cl-C6-alkyl and Cl-C6-alkoxy; in particular R9and R10are H or Cl-C6-alkoxy; more particularly R9and R10are independently H or Cl-C4-alkoxy; still more particularly R9and R10are independently H or Cl-C2-alkoxy; even more particularly R9and R10are H or methoxy; and represents a single bond or is inexistent. In one embodiment, the compounds of Formula II are those wherein LG is selected from and wherein Y is a monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; still more particularly Y is TsO; R8is selected from H, Cl-C6-alkyl and C1-C6- alkoxy; in particular R8is selected from H, Cl-C4-alkyl and Cl-C4-alkoxy; more particularly R8is selected from H, Cl-C2-alkyl and Cl-C2-alkoxy; still more particularly R8is selected from H, methyl and methoxy; R9and R10are independently selected from H, Cl-C6-alkyl and Cl-C6-alkoxy; in particular R9and R10are H or Cl-C6-alkoxy; more particularly R9and R10are independently H or Cl-C4-alkoxy; still more particularly R9and R10are independently H or Cl-C2-alkoxy; even more particularly R9and R10are H or methoxy; and represents a single bond or is inexistent.

[0093] In one embodiment, the compounds of Formula II are those wherein LG is anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; still more particularly Y is TsO. In one embodiment, the compounds of Formula II are those wherein LG is monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; still more particularly Y is TsO; R8is selected from H, Cl-C6-alkyl and Cl-C6-alkoxy; in particular R8is selected from H, Cl-C4-alkyl and Cl-C4-alkoxy; more particularly R8is selected from H, Cl-C2-alkyl and Cl-C2-alkoxy; still more particularly R8is selected from H, methyl and methoxy; R9and R10are independently selected from H, Cl-C6-alkyl and Cl-C6-alkoxy; in particular R9and R10are H or Cl-C6-alkoxy; more particularly R9and R10are independently H or Cl-C4-alkoxy; still more particularly R9and R10are independently H or Cl-C2-alkoxy; even more particularly R9and R10are H or methoxy; and represents a single bond or is inexistent.

[0094] In one embodiment, the compounds of Formula II are those wherein R1is hydroxy-Cl-C2- alkyl, R2is hydroxy-Cl-C2-alkyl and R3is H. In one embodiment, the compounds of Formula II are those wherein R1is H, R2is hydroxy¬

[0095] Cl-C2-alkyl and R3is H.

[0096] In one embodiment, the compounds of Formula II are those wherein R1is hydroxy-Cl-C2- alkyl, R2is hydroxy-Cl-C2-alkyl and R3is selected from -N=C=S, -CH2-N3,

[0097] In one embodiment, the compounds of Formula II are those wherein R1is H, R2is hydroxy- particular R3is selected from

[0098] In one embodiment, the compounds of Formula II are those wherein R1and R2are C(O)NHR4wherein R4is C 1 -C4-alkyl, in particular R4is C 1 -C2-alkyl, more particularly R4is methyl, and R3is H.

[0099] In one embodiment, the compounds of Formula II are those wherein R1is H, R2is C(O)NHR4wherein R4is Cl-C4-alkyl, in particular R4is Cl-C2-alkyl, more particularly R4is methyl, and R3is H. In one embodiment, the compounds of Formula II are those wherein R1and R2are

[0100] C(O)NHR4wherein R4is Cl-C4-alkyl, in particular R4is Cl-C2-alkyl, more particularly R4is methyl, and R3is selected from -N=C=S, -CH2-N3,

[0101]

[0102] 5 In one embodiment, the compounds of Formula II are those wherein R1is H, R2is C(O)NHR4wherein R4is Cl-C4-alkyl, in particular R4is Cl-C2-alkyl, more particularly R4 particular R3is selected from

[0103] In one embodiment, the compounds of Formula II are those wherein R4is methyl. In one embodiment, the compounds of Formula II are those wherein wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, R2is wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, and R3is H. In one embodiment, the compounds of Formula II are those wherein R1is H, R2is wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, and R3is H.

[0104] In one embodiment, the compounds of Formula II are those wherein wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, R2is wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, and R3is C(O)OR7wherein R7is N-succinimidyl.

[0105] In one embodiment, the compounds of Formula II are those wherein R1is H, R2is wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-alkyl, and R3is C(O)OR7wherein R7is N-succinimidyl.

[0106] In one embodiment, particular aryl compounds of the invention are those of formula (Il-a): (Il-a), wherein R1, R2and LG are as defined in Formula (II).

[0107] Particular compounds of Formula (Il-a) are those wherein one or more of R1and R2are defined as follows:

[0108] R1is H or hydroxy-Cl-C2-alkyl; in particular R1is H or hydroxymethyl; and

[0109] R2is hydroxy-Cl-C2-alkyl; in particular R2is hydroxymethyl; and wherein Y is a monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; still more particularly Y is TsO.

[0110] In one embodiment, the compounds of Formula (Il-a) are those wherein R1is H and R2is hydroxy-Cl-C2-alkyl, in particular R2is hydroxymethyl.

[0111] In one emdodiment, the compounds of Formula (Il-a) are those wherein R1and R2are hydroxy-Cl-C2-alkyl, in particular R1and R2are hydroxymethyl.

[0112] In one embodiment, particular aryl compounds of the invention are those of formula (Il-b):

[0113] (Il-b), wherein R1, R2, R3and LG are as defined in Formula (II). Particular compounds of Formula (Il-b) are those wherein one or more of R1, R2, R3and LG are defined as follows:

[0114] R1is H or hydroxy-Cl-C2-alkyl; in particular R1is H or hydroxymethyl;

[0115] R2is hydroxy-Cl-C2-alkyl; R2is hydroxymethyl; wherein Y is a monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; in particular wherein Y is a monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; still more particularly Y is TsO.

[0116] In one embodiment, particular aryl compounds of the invention are those of formula (II-c): wherein R1, R2, R3and LG are as defined in Formula (II). Particular compounds of Formula (I-c) are those wherein one or more of R1, R2, R3and LG are defined as follows:

[0117] R1is H or hydroxy-Cl-C2-alkyl; in particular R1is H or hydroxymethyl;

[0118] R2is hydroxy-Cl-C2-alkyl; R2is hydroxymethyl; wherein Y is a monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; in particular wherein Y is a monovalent anion; in particular Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; more particularly Y is TsO or TfO; still more particularly Y is TsO.

[0119] In one embodiment, particular aryl compounds of the invention are those of formula (Il-d):

[0120] (Il-d), wherein R1, R2, R3and LG are as defined in Formula (II).

[0121] In one embodiment, particular aryl compounds of the invention are those of formula (Il-e):

[0122] (II-e), wherein R1and R2are as defined in Formula (II).

[0123] Particular compounds of Formula (II-e) are those wherein one or more of R1, R2and Y are defined as follows:

[0124] R1is H or hydroxy-Cl-C2-alkyl; in particular R1is H or hydroxymethyl;

[0125] R2is hydroxy-Cl-C2-alkyl; R2is hydroxymethyl;

[0126] Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; in particular Y is TsO or TfO; more particularly Y is TsO. In one embodiment, particular aryl compounds of the invention are those of formula (Il-f) :

[0127]

[0128] (II-f), wherein R1, R2, R3and Y are as defined in Formula (II).

[0129] Particular compounds of Formula (Il-f) are those wherein one or more of R1, R2, R2and Y are defined as follows:

[0130] R1is H or hydroxy-Cl-C2-alkyl; in particular R1is H or hydroxymethyl;

[0131] R2is hydroxy-Cl-C2-alkyl; R2is hydroxymethyl;

[0132] Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4 and BF4; in particular Y is TsO or TfO; more particularly Y is TsO.

[0133] In one embodiment, particular aryl compounds of the invention are those of formula (Il-g):

[0134] (II-g), wherein R1, R2, R3and Y are as defined in Formula (II).

[0135] In one embodiment, particular aryl compounds of the invention are those of formula (Il-h):

[0136] (Il-h), wherein R1, R2, R3and Y are as defined in Formula (II).

[0137] In one embodiment, particular aryl compounds of the invention are those of formula (Il-i):

[0138] (II-i), wherein R1, R2and R3are as defined in Formula (II).

[0139] Particularly preferred aryl compounds of Formula (II) are those listed in Table 2 hereafter:

[0140] Table 2 Particular aryl compounds of Formula (II) are Compounds II- 1 and II-2.

[0141] The aryl compounds of the invention can be prepared by different ways with reactions known by the person skilled in the art, in particular as described by the examples.

[0142] Reaction of an aryl compound carrying a leaving group with astatine

[0143] As detailed above, the invention relates to a method for synthesizing an astatoaryl compound of Formula (I) as defined above comprising the step of reacting an aryl compound carrying a leaving group with astatine, in particular with radioastatine, more particularly with astatine-211 (211At).

[0144] In one embodiment of the method of the invention, the aryl compound carrying a leaving group is a compound of Formula (II) or any of its embodiments as defined above.

[0145] In one embodiment of the method of the invention, the step of reacting an aryl compound carrying a leaving group with astatine is performed with radioisotope astatine-211 (211At).

[0146] In one embodiment of the method of the invention, the step of reacting an aryl compound carrying a leaving group with astatine is performed in the presence of a reducing agent.

[0147] In particular, the reducing agent may be chosen from the group consisting of dithiothreitol (DTT), Na2SOs, Na2S20s, ascorbate, cysteine, triphenylphosphine and hydrazine. More particularly, the reducing agent is dithiothreitol.

[0148] In one embodiment of the method of the invention, the astatine may be present as an astatide salt, in particular an astatide salt of Formula (III):

[0149] A+ 211AF

[0150] (III), wherein

[0151] A is a monovalent cation selected from Na, K, Cs, tetraalkylammonium and tetraalkylphosphonium; in particular A is Na or K; more particularly A is Na. In one embodiment of the method of the invention, the reaction defined above is carried out in a solvent selected from the group consisting of 1,2-dimethoxy ethane, toluene, tetrahydrofurane, acetonitrile, 7V,7V-dimethylformamide, water, ethanol, methanol, acetone and mixtures thereof. In particular, the reaction defined above is carried out in methanol.

[0152] In one embodiment of the method of the invention, the reaction defined above may be carried out in the presence of a base. In particular, the base is selected from the group consisting of NaOH, KOH, LiOH, CsOH, K2CO3, Na2COs, CS2CO3 and mixtures thereof. More particularly, the base is selected from the group consisting of NaOH, KOH, K2CO3, Na2COs and mixtures thereof. Still more particularly, the base is selected NaOH and K2CO3.

[0153] In one embodiment of the method of the invention, the reaction defined above is carried out at a temperature comprised between 20°C and 140°C, in particular between 40°C and 100°C, more particularly between 50°C and 70°C, still more particularly between 55°C and 65°C.

[0154] Reduction step of the astatine

[0155] In one embodiment, the method of the invention previously comprises a step of reduction of astatine. In one embodiment, the reduction is performed in a solution. The solvent may be chosen from acetonitrile, chloroform, an alcohol such as methanol, methyl form am ide, water and mixtures thereof. In particular, the solvent may be acetonitrile, a mixture of acetonitrile and water, or chloroform. More particularly, the solvent may be chloroform.

[0156] In a particular embodiment, the reduction step comprises the following steps: i) preparing a solution of astatine, in particular radioastatine, more particularly astatine-211 (211At), with a solvent chosen from acetonitrile, chloroform, an alcohol such as methanol, N,N-di methyl form am ide, water and mixtures thereof, in particular with acetonitrile, a mixture of acetonitrile and water, or chloroform, more particularly with chloroform; and ii) mixing the solution obtained in step i) with a solution comprising a reduction agent, preferably an aqueous solution, thereby obtaining a solution of an astatide salt.

[0157] In another embodiment, the reduction step comprises the following steps: i) preparing a solution of astatine, in particular radioastatine, more particularly astatine-211 (211At), with a solvent chosen from acetonitrile, chloroform, an alcohol such as methanol, / f, / f-di methyl form am ide, water and mixtures thereof, in particular with acetonitrile, a mixture of acetonitrile and water, or chloroform, more particularly with chloroform; ii) evaporating to dryness the solution obtained in step i), in particular under a stream of N2; and iii) mixing the obtained dry residue of astatine with a solution comprising a reducing agent, in particular with an aqueous solution.

[0158] In one embodiment, the astatide salt is the astatide salt of Formula (III) as defined above.

[0159] In one embodiment, the reduction step is performed with a reducing agent chosen from the group consisting of dithiothreitol (DTT), Na2SOs, Na2S20s, ascorbate, cysteine, triphenylphosphine and hydrazine. In particular, the reducing agent is dithiothreitol.

[0160] In a particular embodiment, the method of the invention comprises the following steps: a) reducing the astatine as defined above, thereby obtaining an astatide salt; b) reacting an aryl compound of Formula (II) as defined above or any of its embodiments with said astatide salt, thereby obtaining the astatoaryl compound of formula (I) as defined above; c) optionally purifying the astatoaryl compound of formula (I), in particular by chromatography.

[0161] Radiolabelling method

[0162] The present invention also relates to a method of synthesizing an astatolabelled biomolecule and / or vector comprising the steps of:

[0163] (i) synthesizing an astatoaryl compound according to the method for synthesizing an astatoaryl compound of Formula (I) of the invention;

[0164] (ii) reacting said astatoaryl compound with a biomolecule and / or a vector carrying a functional group reactive with said astatoaryl compound. In one embodiment, the biomolecule and / or vector is an antibody or a peptide. In particular, the biomolecule and / or vector is an antibody or a peptide targeting tumor cells. More particularly, the biomolecule and / or vector is an antibody selected from 9E7.4, Epratuzumab, Daratumumab, Traztuzumab, J591, Anti CD44v6, Rituximab and HB-7, or a peptide selected from octreotide, octreotate and arginylglycylaspartic acid (RGD peptide). Still more particularly, the biomolecule and / or vector is 9E7.4 or octreotide.

[0165] In one embodiment, the biomolecule and / or vector is an antibody. In particular, the biomolecule and / or vector is an antibody targeting tumor cells. More particularly, the biomolecule and / or vector is an antibody selected from 9E7.4, Epratuzumab, Daratumumab, Traztuzumab, J591, Anti CD44v6, Rituximab and HB-7. Still more particularly, the biomolecule and / or vector is 9E7.4.

[0166] In one embodiment, the biomolecule and / or vector is a peptide. In particular, the biomolecule and / or vector is a peptide targeting tumor cells. More particularly, the biomolecule and / or vector is a peptide selected from octreotide, octreotate and arginylglycylaspartic acid (RGD peptide). Still more particularly, the biomolecule and / or vector is octreotide.

[0167] DEFINITIONS

[0168] The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

[0169] Unless otherwise stated, any reference to compounds of the invention herein, means the compounds as such as well as their pharmaceutically acceptable salts and solvates.

[0170] When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

[0171] The term “unsubstituted” as used herein means that a radical, a group or a residue carries no substituents. The term “substituted” means that a radical, a group or a residue carries one or more substituents.

[0172] The term “halo” or “halogen” refers to the atoms of the group 17 of the periodic table (halogens) and includes in particular fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) atom. Preferred halogen atoms in the context of the invention are fluorine and chlorine, chlorine being particularly preferred.

[0173] The term “alkyl” by itself or as part of another substituent refers to a hydrocarbyl group of Formula CnEEn+i wherein n is a number greater than or equal to 1. Alkyl groups may thus comprise 1 or more carbon atoms and generally, according to this invention comprise from 1 to 12, more preferably from 1 to 8 carbon atoms, and still more preferably from 1 to 6 carbon atoms. Alkyl groups within the meaning of the invention may be linear or branched. Examples of alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopenyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, neohexyl, isohexyl, sec-hexyl and tert-hexyl. Particular examples of alkyl groups in the context of the invention include methyl, ethyl, n-propyl, n-butyl and tert-butyl.

[0174] The term “haloalkyl” alone or in combination, refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non -limiting examples of such haloalkyl groups include chloromethyl, 1- bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1 -trifluoroethyl and the like. A particular example of haloalkyl groups according to the invention is trifluoromethyl.

[0175] The term “heteroatom” as used herein refers to any atom that is not carbon or hydrogen. Non-limiting examples of such heteroatoms include nitrogen, oxygen, sulfur, and phosphorus. Preferred heteroatoms according to the invention are nitrogen, oxygen and sulfur.

[0176] The term “aryl” as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (e.g. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. Examples of aryl groups include but are not limited to phenyl, biphenyl, 1 -naphthyl (or naphthal ene-l-yl), 2-naphthyl (or naphthalene-2-yl), anthracenyl, indanyl, indenyl, 1, 2,3,4- tetrahydronaphthyl. A particular example of aryl groups according to the invention is phenyl.

[0177] The term “heteroaryl” as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together, each ring typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. Examples of heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, furanyl, benzofuranyl, pyrrolyl, indolyl, thiophenyl, benzothiophenyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiazolyl, and benzothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl and tetrazolyl. A particular example of heteroaryl groups according to the invention is pyridinyl.

[0178] The term “astatination” as used herein refers to the synthesis of an astatoaryl compound according to the invention, in particular a compound of Formula (I). In other words, the term “astatination” refers to the radiolabelling of a compound with radioisotope astatine-211 (211At).

[0179] The compounds of the invention include compounds of the invention as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labelled compounds of the invention.

[0180] The present invention will be better understood with reference to the following examples and figures. These examples are intended to be representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.

[0181] FIGURES

[0182] Figure 1: Radiochromatogram of reference compound 18 at t = 0, 3 and 20 h incubation in 1 mM KMnCU Free astatine being retained in the HPLC system during the run, a second run consisting in the injection of sodium sulfite was performed to release and quantify the amount of free At in the injected sample.

[0183] Figure 2: Radiochromatogram of compound of the invention 16 (compound 1-1) at t = 0 and t = 20 h incubation in 1 mM KMnCU and UV chromatogram of iodinated di-acid (2). Figure 3: Comparative release of free211At radiolabeled compounds of the invention 16 and 17, and reference compound 18 in 1 mM KMnCU and acetate buffer pH 4.6 (50 mM) over 20 h.

[0184] Figure 4: Radiochromatograms of rat microsomal stability medium of reference compound 18 at t=0 and t = 20 h incubation.

[0185] Figure 5: Radiochromatograms of rat microsomal stability medium of compound of the invention 16 at t=0 and t = 20 h.

[0186] Figure 6: Comparative release of free211At for radiolabeled compounds of the invention 16 and 17, and reference compound 18 exposed to rat microsomes and NADPH regenerating system in phosphate buffer pH 7.5 (0.5 M) + MgCh (3.3 mM) over 20 h.

[0187] Figure 7: Comparative release of free211At for radiolabeled compounds of the invention 16 and 17, and reference compound 18 exposed to human microsomes and NADPH regenerating system in phosphate buffer pH 7.5 (0.5 M) + MgCh (3.3 mM) over 20 h.

[0188] EXAMPLES

[0189] ABBREVIATIONS

[0190] DCM: dichloromethane;

[0191] DMSO: dimethyl suf oxide;

[0192] DTT: dithiothreitol; eq. / equiv.: equivalent;

[0193] HPLC: high-performance liquid chromatography;

[0194] / 7 / -CPB A: meta-chloroperoxybenzoic acid;

[0195] NMR: nuclear magnetic resonance; ppm: parts per million; PTSA: p-toluenesulfonic acid;

[0196] RCY : radiochemical yield;

[0197] ROS: reactive oxygen species;

[0198] TFA: trifluoroacetic acid;

[0199] THF : tetrahydrofurane;

[0200] TLC: thin-layer chromatography;

[0201] IR: retention time;

[0202] UV: ultraviolet;

[0203] [211At]SAB: N-succinimidyl 3-[211At]astatobenzoate.

[0204] SYNTHESIS

[0205] 1. Material and instrumentation

[0206] Commercial Reagents and solvents were purchased from Merck, Fisher Scientific, TCI or Fluorochem. Deuterated solvents were provided from Sigma Aldrich.

[0207] Reactions were monitored by thin-layer chromatography (TLC) using 60 F254 silica gel plates on aluminium support (Merck) and revealed by UV lamp (254 nm). A Puriflash 430 (Interchim) with 30 pm silica pre-packed columns was used to purify the compounds.

[0208] NMR analyses were performed with a Bruker AC spectrometer at 400 MHz (1H) or 101 MHz (13C). Chemical shifts (5) are expressed in part per million (ppm) relative to deuterated solvents, CDCh: 7.26 ppm, DMSO-d6: 2.50 ppm, CD3CN: 1.94 ppm (CDs^CO: 2.50 ppm. The multiplicity is reported with the following symbols: s (singlet), d (doublet), t (triplet), q (quadruplet) and m (multiplet), br (broad signal). Mass spectrometry analyses were operated on a Synapt G2 HRMS Q-TOF mass spectrometer (Waters) equipped with an electrospray ionization (ESI) interface operating in the positive mode.

[0209] 2. Synthesis of aryliodonium salts EXAMPLE 1

[0210] Procedure for preparation of precursors (2,6-bis(hvdroxymethyl)phenyl)(4- methoxyphenylliodonium 4-methylbenzenesulfonate II-l

[0211] Preparation of (2,6-bis(hydroxymethyl)phenyl)(4-methoxyphenyl)iodonium 4- methylbenzenesulfo-nate II-l (compound 6) for [211At](2-astato-l,3-phenylene)dimethanol production was achieved in 5 steps (Scheme 1). The first step involved the oxidation of 2- iodo-l,3-dimethylbenzene (1) using hot KMnCU, leading to the corresponding di-carboxylic acid (2). (2) was then esterified to the corresponding methyl ester (3) via formation of an acid chloride intermediate. Next, (3) was reduced in the presence of LiBEL to form the corresponding alcohol (4). Intermediate (4) is also an iodinated reference that serves as a surrogate for astatine retention index comparison of211At-labelled compounds. The next step consisted in protecting the hydroxyl groups with acetyl using acetic anhydride to form the di-protected alcohol (5). Finally, activation into an iodonium salt, was performed using m- CPBA to activate the iodine followed by addition of PTSA.H2O and anisole to form the iodonium salt (6).

[0212] 44%

[0213] Scheme 1

[0214] 2-iodo-isophtalic acid (2). A tert-BuOH / water (50 mL / 40 mL) mixture was added to a flask containing the commercially available 2-iodo-m-xylene 1 (3.00 g, 1 eq.). A first portion of KMnO4 (5.10 g, 2.5 eq.) was added to the solution and stirred vigorously at room temperature. The medium was stirred for 2 h at 70°C and, after cooling to room temperature, the second portion of KMnC (5.10 g, 2.5 eq.) was added. The medium was stirred at 70°C overnight. The medium was then hot-filtered over a frit funnel and the solid rinsed with water. The filtrate was acidified to pH 2 with 37% hydrochloric acid. The product was extracted with 3 x 25mL of ethyl acetate, then the organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give product 3 as a white solid (3.32 g, 88%).

[0215] 'HNMR (400 MHz, DMSO-d6): 8 (ppm) 13.50 (s, 2H), 7.60-7.55 (m, 2H), 7.51 (dd, J= 8.6, 6.4 Hz, 1H).13C NMR (101 MHz, DMSO-de): 6 (ppm) 169.2, 141.2, 129.6, 128.2, 91.0.

[0216] 2-iodo-isophtalic acid dimethyl ester (3). Thionyl chloride (5 mL) was added to a flask containing the carboxylic acid derivative 2 (570 mg, 1 eq.) under an inert atmosphere. The medium was stirred at 70°C overnight. Excess thionyl chloride was removed by distillation under reduced pressure. The medium was then placed in an ice bath and methanol (10 mL) and triethylamine (2 mL) were added slowly, then stirred at room temperature overnight. The reaction was quenched with water, and product extracted with di chloromethane. Organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica cartridges (eluent: chloroform / methanol) to give product 3 as a yellow oil (490 mg, 79%).

[0217] 'HNMR (400 MHz, MeOD): 5 (ppm) 7.62-7.58 (m, 2H), 7.53-7.46 (m, 1H), 3.92 (s, 6H).

[0218] 13C NMR (101 MHZ, MeOD): 5 (ppm) 169.8, 141.7, 131.9, 129.4, 91.6, 53.3.

[0219] (3-hydroxymethyl-2-iodo-phenyl)-methanol (4). A solution of methyl ester 3 (1.02 g, 1 eq.) in anhydrous THF (19 mL) was placed in a flask under inert atmosphere. A solution of LiBH4 (2 M in THF, 3 eq.) was added dropwise at 0°C with vigorous stirring. The medium was then stirred at room temperature for one night. The medium was placed in an ice bath and the reaction quenched by gently adding 1 M HC1 until end of gas evolution, then the solvent was evaporated. The residue was purified by flash chromatography on silica cartridges (eluent: C^CL / methanol) to give product 4 as a white solid (606 mg, 72%).

[0220] 'HNMR (400 MHz, MeOD): 5 (ppm) 7.44-7.31 (m, 3H), 4.62 (s, 4H).

[0221] 13C NMR (101 MHZ, MeOD): 5 (ppm) 144.8, 129.2, 127.7, 100.3, 70.0.

[0222] Acetic acid 3-acetoxymethyl-2-iodo-benzyl ester (5). The alcohol derivative 4 (100 mg, 1 eq.) was dissolved in anhydrous THF (5 mL) in a dry flask under an inert atmosphere. The medium was placed at 0°C, then tri ethylamine (170 pL, 3 eq.) and acetic anhydride (93 pL, 2.5 eq.) were added and stirred at room temperature for 5 days. The solvent was evaporated, the solid taken up in dichloromethane and washed with 10 mL of water and 10 mL of brine. The aqueous phase was extracted with 15 mL DCM. The organic phase was dried over MgSO4, filtered and the solvent evaporated to give product 5 as a yellow oil which crystallizes at room temperature (127 mg, 96%).

[0223] 'HNMR (400 MHz, CDC13): 8 (ppm) 7.39-7.29 (m, 2H), 5.17 (s, 4H), 2.15 (s, 6H).13C NMR (101 MHz, CDC13): 6 (ppm) 170.6, 139.5, 129.1, 128.5, 102.7, 70.8, 21.0.

[0224] (2,6-bis-acetoxymethyl-phenyl)-(4-methoxy-phenyl)-iodonium 4-methylbenzenesulfo- nate (II-l). The protected alcohol derivative 5 (166 mg, 1 eq.) was dissolved in chloroform (15 mL) and the m-CPBA (99 mg, 1.2 eq.) was placed in a dry flask under inert atmosphere. The solution was stirred at room temperature for 15-20 min, then PTSA.H2O (109 mg, 1.2 eq.) and anisole (280 pL, 5.4 eq.) were added. The medium was heated to 40°C for 2h30. The solvent was evaporated. The solid was taken up in the minimum amount of methanol, then diethyl ether was added until a cloud forms and placed in the fridge for one night. The liquid phase was separated from the brown aggregate formed, which was redissolved in minimal methanol. Ether was added until cloudy, then the flask was placed in the fridge until crystals appear. The crystals were filtered and rinsed with a little cold diethyl ether, then dried to give the iodonium salt precursor II-l as brown crystals (114 mg, 44%).

[0225] XH NMR (400 MHz, MeOD): 5 (ppm) 8.11-8.03 (m, 2H), 7.73-7.67 (m, 2H), 7.70-7.62 (m, 1H), 7.59 (d, J= 8.2 Hz, 2H), 7.23 (d, J= 8.2 Hz, 2H), 7.07-6.99 (m, 2H), 4.80 (s, 4H), 3.83 (s, 3H), 2.37 (s, 3H).

[0226] 13C NMR (101 MHz, MeOD): 5 (ppm) 164.3, 145.7, 143.6, 141.6, 138.4, 134.4, 131.2, 129.8, 127.0, 120.3, 118.6, 102.8, 67.2, 56.3, 21.3.

[0227] HRMS: Ci5Hi6O3rcalc: 371.0144, found: 371.0144.

[0228] EXAMPLE 2

[0229] Procedure for preparation of precursor ((2-(hvdroxvmethvl)phenvD(4- methoxvphenvDiodonium 4-methvlbenzenesulfonate II-2

[0230] ((2-(hydroxymethyl)phenyl)(4-methoxyphenyl)iodonium 4-methylbenzenesulfonate II-2 (compound 12) comprising a single hydroxyl group was also prepared as well as the iodinated reference (10) following the same sequence starting from l-iodo-2-m ethylbenzene (7) (Scheme 2).

[0231] Scheme 2

[0232] 2-iodo-benzoic acid (8). A tert-BuOH / water (60 mL / 40 mL) mixture was added to a flask containing the commercially available starting material l-iodo-2-methylbenzene 7 (5.00 g, 1 eq.). A first portion of KMnC (4.50 g, 1.25 eq.) was added to the medium and stirred vigorously at room temperature. The medium was stirred for 2 h at 70°C and then, after cooling to room temperature, the second portion of KMnC (4.50 g, 1.25 eq.) was added. The medium was stirred at 70°C overnight. The medium was hot-filtered over frit funnel and the solid rinsed with water. The filtrate was acidified to pH 2 with 37% hydrochloric acid. The product was extracted with 3 x 35 mL of ethyl acetate, then the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to give product 8 as a brown solid (1.05 g, 18%).

[0233] 'H NMR (400 MHz, DMSO): 5 (ppm) 13.33 (s, 1H), 7.98 (dd, J= 7.9, 1.0 Hz, 1H), 7.70 (dd, J= 7.7, 1.7 Hz, 1H), 7.47 (td, J= 7.6, 1.1 Hz, 1H), 7.23 (td, J= 7.6, 1.7 Hz, 1H).13C NMR (101 MHz, DMSO): 5 (ppm) 168.1, 140.5, 136.9, 132.4, 130.0, 128.2, 94.0. 2-iodo-benzoic acid methyl ester (9). Thionyl chloride (10 mL) was added to a flask containing the carboxylic acid derivative 8 (1.00 g, 1 eq.) under an inert atmosphere. The medium was stirred at 70°C during 4 h. Excess thionyl chloride was removed by distillation under reduced pressure. The medium was then placed in an ice bath and methanol (10 mL) and triethylamine (5 mL) were added slowly, then stirred at room temperature for 2 days. The reaction was quenched with water and product extracted with 2 x 15mL of dichloromethane. Organic layer was washed with 20 mL of water and 20 mL of brine and dried over anhydrous magnesium sulfate. After filtration and solvent evaporation, the product was purified by flash chromatography on silica cartridge (eluent: CELCh / methanol) to give product 9 as a colorless oil (1.05 g, 99%).

[0234] 1HNMR (400 MHz, MeOD): 5 (ppm) 8.01 (dd, = 8.0, 1.2 Hz, 1H), 7.74 (ddd, J = 7.8, 3.0, 1.8 Hz, 1H), 7.52-7.43 (m, 1H), 7.26-7.19 (m, 1H), 3.91 (d, J= 0.9 Hz, 3H).

[0235] 13C NMR (101 MHZ, CDCh): 6 (ppm) 167.1, 141.5, 135.3, 132.8, 131.1, 128.0, 94.2, 52.6.

[0236] (2-iodo-phenyl)-methanol (10). A solution of methyl ester 9 (800 mg, 1 eq.) in anhydrous THF (15 mL) was placed in a flask under inert atmosphere. A solution of LiBH4 (100 mg in 5 mL THF, 1.5 eq.) was added dropwise at 0°C with vigorous stirring. The medium was then stirred at 40°C for one day. The medium was placed in an ice bath and the reaction quenched by gently adding 0.4 M HC1 to pH 6-7, then the solvent was evaporated. The product was purified by flash chromatography on silica a cartridge (eluent: chloroform / methanol) to give the products 10 as a white solid (580 mg, 81%).

[0237] 'H NMR (400 MHz, DMSO): 5 (ppm) 7.80 (dd, J= 7.9, 1.2 Hz, 1H), 7.51-7.45 (m, 1H), 7.41 (td, J= 7.4, 1.2 Hz, 1H), 7.02 (td, J = 7.5, 1.8 Hz, 1H), 5.48 (t, J = 5.5 Hz, 1H), 4.40 (d, J = 5.0 Hz, 2H).

[0238] 13C NMR (101 MHZ, DMSO): 6 (ppm) 143.7, 138.4, 128.8, 128.2, 127.7, 96.9, 67.3.

[0239] Acetic acid 2-iodo-benzyl ester (11). The alcohol derivative 10 (580 mg, leq.) was dissolved in anhydrous THF (20 mL) in a dry flask under an inert atmosphere. The medium was placed at 0°C, then triethylamine (0.52 mL, 1.5 eq.) and acetic anhydride (0.30 mL, 1.3 eq.) were added and stirred at room temperature for 4 days. The solvent was evaporated, the solid taken up in dichloromethane and washed with 2 * 20 mL of water. The organic phase was dried over MgSO4, filtered and the solvent evaporated. The product was purified by flash chromatography on silica cartridges (eluent: DCM / Heptane) to give the product 11 as a colorless oil (0.63 g, 92%).

[0240] 'HNMR (400 MHz, CDC13): 8 (ppm) 7.89-7.83 (m, 1H), 7.41-7.31 (m, 2H), 7.07-6.99 (m, 1H), 5.12 (s, 2H), 2.15 (s, 3H).

[0241] 13C NMR (101 MHZ, CDCI3): 6 (ppm) 170.7, 139.7, 138.5, 130.0, 129.6, 128.5, 98.5, 70.2, 21.0.

[0242] ((2-hydroxymethyl)phenyl)(4-methoxyphenyl)iodonium 4-methylbenzenesulfonate (II- 2). The protected alcohol derivative 11 (300 mg, 1 eq.) was dissolved in DCM (10 mL) in a dry flask under inert atmosphere and the m-CPB A (230 mg, 1.2 eq.) was added. The solution was stirred at room temperature for 15-20 min, then PTS A.H2O (250 mg, 1.2 eq.) and anisole (640 pL, 5.4 eq.) were added. The medium was heated to 40°C for 2h30. The solvent was evaporated and the residue was purified by flash chromatography on silica cartridges (eluent: DCM / methanol) to give the iodonium salt precursor II-2 as a brown oil-solid (247 mg, 44%).

[0243] 'HNMR (400 MHz, MeOD): 6 (ppm) 8.12-8.04 (m, 2H), 7.68 (d, J= 8.2 Hz, 2H), 7.58-7.47 (m, 2H), 7.36-7.29 (m, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.18-7.11 (m, 2H), 4.90 (s, 2H), 3.90 (s, 3H), 2.36 (s, 3H).

[0244] 13C NMR (101 MHz, MeOD): 6 (ppm) 165.0, 142.2, 141.6, 140.3, 132.6, 132.5, 132.1, 131.0, 129.8, 127.0, 119.2, 114.6, 101.2, 65.5, 56.4, 21.3.

[0245] HRMS: Ci4Hi4O2rcalc: 341.0038, found: 341.0041.

[0246] COMPARATIVE EXAMPLE

[0247] Procedure for preparation of 4-methylbenzenesulfonate

[0248] For comparison with a standard astatoaryl compounds (i.e without hydrogen-bond donor next to the At), an analogue of the N-succinimidyl 3-[211At]astatobenzoate ([211At]SAB) prosthetic group (most frequently used prosthetic group for protein labelling (Vaidyanathan, G. etal., Cancer Biother. Radiopharm. 2020, 35, 511-519) was designed. This compound is comprised of an ethyl amide function in meta position to the astatine atom to reproduce the SAB electronic properties once conjugated to the amino group of lysine residue. Its precursor (15) was prepared in 2 steps (Scheme 3) from 3-iodobenzoic acid (13). The first step consisted in the formation of the acid chloride intermediate followed by substitution by ethylamine to form the desired ethyl amide (14) that would also serve as a iodinated reference of astatinated analogue. Conversion into iodonium salt (15) was then performed using the same method than above.

[0249] Scheme 3

[0250] 3-iodo-N-ethylbenzamide (14). Thionyl chloride (5 mL) iswas added to a dry, inert flask containing commercially available 3-iodobenzoic acid 13 (2.00 g, 1 eq.). The medium was heated under reflux and stirred for 3 h. Excess thionyl chloride was evaporated and anhydrous THF (10 mL) was added to the acid chloride. The medium was placed in an ice bath and triethylamine (1.36 mL, 1.2 eq.) followed by ethylamine (2 M solution in THF, 4.80 mL, 1.2 eq.) were added slowly. The medium was left to stir at room temperature under argon for approximately 16 h. The solvent was evaporated, the solid taken up in DCM, washed with 25 mL of 2 M HC1, 25 mL of saturated ISfeCCL and finally 25 mL of brine. The organic phase was dried over MgSCh, filtered and evaporated. The product was purified by flash chromatography on silica cartridges (Eluent: DCM / AcOEt) to give the product 14 as a brown-orange solid (1.46g, 66%).JH NMR (400 MHz, CDC13): 6 (ppm) 8.08 (t, J= 1.6 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.74- 7.68 (m, 1H), 7.16 (t, J= 7.8 Hz, 1H), 6.14 (s, 1H), 3.48 (p, J= 7.1 Hz, 2H), 1.25 (t, J= 7.3 Hz, 3H).

[0251] 13C NMR (101 MHZ, MeOD): 6 (ppm) 168.3, 141.5, 137.9, 137.3, 131.3, 127.5, 94.7, 35.9, 14.8.

[0252] ((3-ethylcarbamoyl)phenyl)(4-methoxy-phenyl)iodonium 4-methylbenzenesulfonate (II-3). Compound 14 (600 mg, 1 eq.) was dissolved in DCM (20 mL) in a dry flask under an inert atmosphere and m-CPBA (450 mg, 1.2 eq.) was added. The solution was stirred at room temperature for 15-20 min, then PTSA.H2O (500 mg, 1.2 eq.) and anisole (1.28 mL, 5.4 eq.) were added. The medium was heated to 40°C for 2 h. The solvent was evaporated and solid was taken up in a little methanol, a white solid remains partially insoluble. The solid was filtered and the filtrate evaporated. The brown solid in the filtrate was taken up again in MeOH to give another partially soluble white solid (same operation as above, until no white solid remains). When all the white solid has been recovered, the solid of each extraction was taken up in methanol and recrystallized with diethylether to give the precursor II-3 as white crystals (903 mg, 75%).

[0253] XH NMR (400 MHz, MeOD): 5 (ppm) 8.54 (t, J= 1.7 Hz, 1H), 8.25 (ddd, J= 8.1, 1.9, 0.9 Hz, 1H), 8.14-8.08 (m, 2H), 8.08-8.03 (m, 1H), 7.73-7.67 (m, 2H), 7.60 (t, J= 7.9 Hz, 1H), 7.23 (d, J= 7.9 Hz, 2H), 7.11-7.03 (m, 2H), 3.85 (s, 3H), 3.41 (q, J= 7.3 Hz, 2H), 2.37 (s, 3H), 1.22 (t, J = 7.3 Hz, 3H).

[0254] 13C NMR (101 MHz, MeOD): 5 (ppm) 167.0, 164.7, 143.7, 141.6, 139.3, 138.7, 138.4, 135.0, 133.0, 131.7, 129.8, 127.0, 119.0, 116.6, 104.5, 56.4, 36.1, 21.3, 14.7.

[0255] HRMS: Ci6Hi7NO2I+calc: 382.0304, found: 382.0302.

[0256] RADIOCHEMISTRY

[0257] 1.211At Radiolabelling of aryliodonium salts

[0258] 1.1. Procedure for the preparation of nucleophilic At211At was produced at the Arronax cyclotron facility using the209Bi(a,2n)211At reaction and recovered from the irradiated target in chloroform using a dry distillation protocol adapted from the procedure previously reported in Lindegren etal.,Appl. Radiat. Isot. 2001, 55, 157- 160. Before use, the211At solution was reduced to dryness under a gentle stream of nitrogen. HPLC analyses were performed on a Waters Alliance e2695 system equipped with a BetaRAM Radio Flow Detector (LabLogic) and a C-18 column (Spherisorb ODS2 5 1 4.6 mm 25 cm, Waters) with the flow rate set at 1.20 mL / min with the following gradient: t = 0: 90% A, 10% B; t = 7 min: 30% A, 70% B; t = 11-15 min: 100% B with A = H2O with 0.05% TFA and B = CH3CN with 0.05% TFA. To quantify free astatine that remain in the HPLC system during the elution, 50 pL of sodium sulfite solution (10 mg.mL'1) were injected after each analysis to release free astatine from the HPLC system with the flow rate set at 1.20 mL / min with the following gradient: t = 0: 90% A, 10% B; t = 2-6 min: 100% B with A = H2O with 0.05% TFA and B = CH3CN with 0.05% TFA. The non-radioactive iodinated compounds were analyzed using this HPLC system and their retention times were used as references for identification of their astatinated analogues.

[0259] 1.2. General procedure for astatination of aryliodonium salts precursors

[0260] Chloroform211At solution was evaporated to dryness under a gentle stream of nitrogen. The dried astatine was reduced by the addition of 5 pL of DTT solution (10 mg.mL'1). After stirring for 1 minute at room temperature, 95 pL of a solution of the precursor in methanol (2.5 mM) was added to the medium and placed at 60°C for 30 minutes. After HPLC and radio-TLC analysis of the medium, it was diluted in 1 mL of water and deposited on a Sep- Pak Plus Long C18 column (from Waters) previously conditioned by passing 10 mL of CH3CN and 10 mL of water. Excess precursor was removed by passing 3 mL of 95 / 5 H2O / CH3CN, then the radiolabeled compound was recovered by passing 1 mL fractions of 1 : 1 H2O / CH3CN. The fractions containing the pure radiolabeled compound were combined and diluted in 20 mL of water, and deposited on a Sep-Pak Plus Light C18 column (from Waters) previously conditioned by passing 5 mL of CH3CN and 5 mL of water to concentrate the medium. After deposition, the column was air-dried and the pure radiolabeled compound was eluted by passing 500 pL of CH3CN. The acetonitrile was evaporated to about half of its initial volume under a stream of dry nitrogen. Compound degradation (released astatine) was quantified by integration of peak areas by the ratio of free astatine (outgoing peak to injection peak when present + sulfite rinse) to the sum of radiochromatogram areas (free astatine area + area of peaks corresponding to astatoaryl compounds).

[0261] 2. Results

[0262] 211At radiolabelling of aromatic compounds with aryliodonium salts was performed according to the General procedure. The radiochemical yield (RCY) was determined by HPLC of the crude product. The results are presented in Table 3 below.

[0263] Table 3

[0264] STABILITY ASSAYS 1. Stability assays in oxidizing / acidic medium

[0265] A vial was filled with 918 pL of acetate buffer pH 4.7 (50 mM) and 32 pL of KMnO4 solution (31.6 mM). After gentle agitation, 50 pL of pure radiolabeled compound was added to the medium, which is left to incubate at room temperature under vigorous agitation. The medium was analyzed by HPLC at 15min, Ih, 3h, 5h and 20h, by withdrawing a small quantity of the medium (5 pL - 10 pL) diluted in water into an HPLC vial.

[0266] 2. Stability assay in microsomal medium (rat and human} In a vial containing 200 pL of phosphate buffer pH 7.4 (0.5 M) + MgCh (3.3 mM), add 50 pL of NADPH regeneration system A and 10 pL of system B (NADPH system from Promega). 40 pL (2 x 20 pL with stirring between each addition) of pure radiolabeled compound in CH3CN and 675 pL of purified water were added to the medium. The medium was pre-incubated for 5 min at 37°C. Microsome (rat or human from Sigma-Aldrich) was added (25 pL - 10 mg / mL protein) and the medium was incubated at 37°C in an oven. Analysis: 100 pL of medium was sampled at 15min, Ih, 3h, 5h and 20h and the enzymatic reaction rapidly quenched by adding 200 pL of ice-cold MeOH. The sample was diluted with 600 pL of water and centrifuged (4000 rpm, 5 min). The supernatant was analyzed by HPLC.

[0267] 3. Results

[0268] 3.1. In vitro stability studies

[0269] In order to determine the potential stability gain compared to [211At] SAB analogue (18), biochemical stability assays were performed. These have been chosen to reproduce certain conditions encountered in vivo, particularly during cellular internalization by passage in lysosomes or to reproduce the metabolization of compounds. To quantify the degradation of the compounds, the amount of free astatine resulting from the break of the carbon-astatine bond was determined by HPLC analysis of stability assay medium.

[0270] 3.1.1. Stability in KMnCh solution

[0271] In order to reproduce the cell internalization conditions in vivo, a stability assay in oxidizing and acidic medium was performed according to the conditions described by Teze, D. et al., Sci. Rep. 2017, 7, 2579. This assay uses potassium permanganate as a strong oxidant in acid acetate buffer (pH 4.6). These oxidizing and acidic conditions aim to mimic the conditions found in lysosomes encountered when internalization within cells occurs, and where the presence of reactive oxygen species (ROS) plays the role of a strong oxidant with acidic pH values (~ 4.7). Under these conditions, a strong degradation of 3 -ethyl astatobenzoate with more than 50% free astatine released after 15h incubation was reported. Accordingly, the same conditions were applied to the [211At]SAB analogue (18), leading to a rapid degradation of the C-At bond highlighted by free astatine released in the medium and 100% free astatine observed after 20h (Figure 1).

[0272] Conversely, results observed with compounds functionalized by hydrogen donors showed a significant improvement in stability, in particular the di-functionalized compound (16) with only 1-2% free astatine after 20h incubation and 10% for the mono-functionalized (17) (Figure 3). Interestingly, compounds 16 (Figure 2) and 17 were converted into a new, more polar compound. The most likely hypothesis for the generation of these new, more polar species is the oxidation of alcohols in the benzyl position. To confirm this hypothesis, the di-acid compound (2) was injected in the HPLC system. Retention time was nearly identical to the major formed astatine species (Figure 2).

[0273] Overall, these results show a strong stabilizing effect provided by hydroxyl groups compared with the SAB analog (Figure 3), with stability increasing as a function of the number of donors.

[0274] 3.1.2. Metabolization assay

[0275] In order to predict the metabolism of radiolabeled compounds against oxydative enzymes found in vivo, assays were carried out in the presence of human and rat microsomes. In this assay, adapted from previously reported procedure (Schmitt 2017), cytochrome P450 was used. These enzymes found in liver are heavily involved in the oxidative degradation of exogenous molecules. Assays were carried out on rat and human liver microsomes under physiological conditions (pH 7.5 - 37°C) with the addition of a NADPH oxi dative / redox catalytic system to regenerate CYP450 enzyme activity. This system is also involved in the generation of ROS in vivo.

[0276] RadioHPLC analyses of medium show a significant dehalogenation of the [211At] SAB analog (18) with 33% free211At in rat microsomes and 6-7% in humans after 20 h. The formation of several metabolites is also observed with the generation of several astatoaryl compounds, certainly due to redox reactions on the amide function (Figure 4).

[0277] For compounds functionalized with hydroxyl functions, a lower release of free astatine was observed: 2-3% for rats and humans with (16), and 10-11% for rats and 5-6% for humans with (17). In contrast to the [211At]SAB analog (18), no other species were formed during the assay (Figure 5).

[0278] As for KMnCU assay, results show a significant improvement in the stability of compounds functionalized with hydroxyl functions in the vicinity of the astatine, with a gradual effect of the number of hydrogen bond donors (Figure 6 and 7). The alcohols positioned in the ortho position of the astatine may act as a shield against the reactive sites of the CYP450 responsible for At oxidation and subsequent C-At bond breakage.

Claims

CLAIMS1. An astatoaryl compound of Formula (I):(I), whereinR1is selected from H, hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl, and wherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2-R2is selected from hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl andwherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2- alkyl;2. The astatoaryl compound according to claim 1, wherein R4is Me.

3. The astatoaryl compound according to claim 1 or 2, having the Formula (la):(la), wherein R1and R2are as defined in claim 1.

4. The astatoaryl compound according to claim 1 or 2, having the Formula (lb):(lb),wherein R1and R2are as defined in claim 1.

5. The astatoaryl compound according to claim 1, selected from the group consisting of:(2-(astato-211 At)- 1 , 3 -phenylene)dimethanol ;(2-(astato-211 At)phenyl)methanol; and2,5-dioxopyrrolidin-l-yl 4-(astato-21 lAt)-3,5-bis(hydroxymethyl)benzoate.

6. A compound of Formula (II):(II), whereinR1is selected from H, hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl andwherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2- alkyl;R2is selected from hydroxy-Cl-C2-alkyl, C(O)NHR4wherein R4is Cl-C4-alkyl andwherein R5is hydroxy-Cl-C2-alkyl and R6is H or hydroxy-Cl-C2- alkyl;whereinY is a monovalent anion;M is Si or Sn;R7is Cl-C6-alkyl; R8is selected from H, Cl-C6-alkyl and Cl-C6-alkoxy;R9and R10are independently selected from H, Cl-C6-alkyl and Cl-C6-alkoxy; and represents a single bond or is inexistent.

7. The compound according to claim 6, wherein R4is Me.

8. The compound according to claim 6 or 7, wherein Y is selected from TfO, CF3COO, TsO, MsO, Br, Cl, SO4and BF4.

9. The compound according to claim 6, selected from the group consisting of:(2,6-bis(hydroxymethyl)phenyl)(4-methoxyphenyl)iodonium 4-methylbenzenesulfo- nate;((2-(hydroxymethyl)phenyl)(4-methoxyphenyl)iodonium 4-methylbenzenesulfonate; and2,5-dioxopyrrolidin-l-yl 3,5-bis(hydroxymethyl)-4-(4,4,5,5-tetramethyl-l,3,2- di oxab orolan-2-y l)b enzoate .

10. A method for synthesizing an astatoaryl compound of Formula (I) according to any one of claims 1 to 5 comprising the step of reacting an aryl compound carrying a leaving group with astatine.

11. The method according to claim 10, wherein the aryl compound carrying a leaving group is a compound of Formula (II) according to any one of claims 6 to 9.

12. The method according to claim 10 or 11, wherein the step of reacting an aryl compound carrying a leaving group with astatine is performed in the presence of a reducing agent.

13. The method according to claim 12, wherein the reducing agent is dithiothreitol.

14. A method of synthesizing an astatolabelled biomolecule and / or vector comprising the steps of:(i) synthesizing an astatoaryl compound of Formula (I) according to the method according to any one of claims 10 to 13; and(ii) reacting said astatoaryl compound with a biomolecule and / or a vector carrying a functional group reactive with said astatoaryl compound.

15. The method according to claim 14, wherein the biomolecule and / or a vector is an antibody or a peptide, preferably the biomolecule and / or vector is an antibody or a peptide targeting tumor cells.

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