Photochemically induced conjugation of radiometals to small molecules, peptides and nanoparticles in a simultaneous one-pot reaction
AssigneeUniversitäT ZüRich
InventorsJason Philip HOLLAND, Malay PATRA
Life of this patent
Estimating the term…
Abstract
The invention relates to a method for labeling a target compound with a radiometal by photochemically induced conjugation. Furthermore, a chelating compound for use in said method is provided. The chelating compound is characterized by an arylazide moiety which can be photo-conjugated to a target compound and a chelator moiety which can be radiolabelled. The photo-conjugation and radiolabelling are both performed at basic pH performed in a simultaneous one-pot reaction.
Claims15
A method for preparing a photoradiolabelled compound comprising
- i. providing a reaction mixture comprising
- at least one chelating compound, and
- at least one target compound B comprising an amine and/or thiol and/or carboxylate moiety, particularly an amine and/or thiol moiety, and
- at least one radioactive ion of a radionuclide,
- ii. performing photoconjugation and radiolabelling in a photoradiolabelling step by
- adjusting the pH to pH>7, in particular pH>8, more particularly pH 8 to 11
- irradiation of the reaction mixture with light at a wavelength selected from 200 nm to 420 nm,
- wherein the chelating compound is a compound of formula 1,
- wherein
- A is a chelator suitable for coordinating an ion of a radionuclide at basic pH,
- L is a linker with z being 0 or 1,
- R1 is independently from each other selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, —NH2, —NHR2, —NR2R3, —OH, —OR4, —SR4, —CF3, —CH2F, —CHF2, —CH2—CF3, —CH2—CH2F, —CH2—CHF2, —SOCF3, —SO2CF3, —SC2—NR2R3, —CN, —NO2, —F, —Cl, —Br or —I, in particular —OH, —CN, —NO2, —F, —Cl, —Br, or —I, with
- R2 and R3 being independently selected from C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl,
- 4 being selected from C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl which may optionally be substituted with —F, —Cl, —Br or —I
- n is 0, 1, 2 or 3, in particular 0 or 1, more particularly 0, and
- R1 and —N3 are positioned in such a way that at least one of the positions 2 to 6 of the phenyl moiety that are next to —N3 is unsubstituted.
The method according to any one of the preceding claims, wherein the radionuclide is selected from 43Sc, 44Sc, 47Sc, 45Ti, 51Cr, 51Mn, 52Mn, 52mMn, 52Fe, 55Co, 57Ni, 60Cu, 61Cu, 62Cu, 64Cu, 67Cu, 65Zn, 66Ga, 67Ga, 68Ga, 69Ge, 71As, 72As, 74As, 76As, 77As, 82Rb, 82mRb, 82Sr, 83Sr, 89Sr, 86Y, 90Y, 89Zr, 97Zr, 90Nb, 94mTc, 99mTc, 97Ru, 105Rh, 111Ag, 110mIn, 111In, 117mSn, 153Sm, 149Tb, 152Tb, 155Tb, 161Tb, 166Ho, 165Er, 177Lu, 178Ta, 186Re, 188Re, 192Ir, 195mPt, 198Au, 197mHg, 201Tl, 212Pb, 212Bi, 213Bi, 211At, 223Ra, 255Ac, in particular from 153Sc, 44Sc, 47Sc, 60Cu, 61Cu, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 86Y, 90Y, 89Zr, 99mTc, 111In, 153Sm, 149Tb, 152Tb, 155Tb, 161Tb, 77Lu, 186Re, 188Re, 212Pb, 212Bi, 213Bi, 223Ra, 255Ac.
The method according to any one of the preceding claims, wherein a co-ligand is added to the reaction mixture, in particular acetate, oxalate or chloride.
A chelating compound comprising formula 2,
- wherein
- A is a chelator suitable for coordinating an ion of a radionuclide, particularly at basic pH,
- L is a linker with z being 0 or 1,
- R1 is independently from each other selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, —NH2, —NHR2, —NR2R3, —OH, —OR4, —SR4, —CF3, —CH2F, —CHF2, —CH2—CF3, —CH2—CH2F, —CH2—CHF2, —SOCF3, —SC2CF3, —SC2—NR2R3, —CN, —NO2, —F, —Cl, —Br or —I, in particular ——OH, —OR4, —CN, —NO2, —F, —Cl, —Br, or —I, with
- R2 and R3 being independently selected from C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl,
- R4 being selected from C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl which may optionally be substituted with —F, —Cl, —Br or —I,
- n is 0, 1, 2 or 3,
- wherein R1 and —N3 are positioned in such a way that at least one of the positions 2 to 6 of the phenyl moiety that are next to —N3 is unsubstituted,
- with the proviso that in case of z being 0, A is not EDTA, and
- with the proviso that in case of z being 1, A is not DTPA.
A radiolabelled intermediate compound comprising formula 3,
- wherein
- A* is a chelator bound to a radionuclide by coordinate bonds, and
- L, z, R1 and n are defined as described above.
A photoconjugated intermediate compound comprising formula 4a, 4b, 4c, 4d or 4e,
- wherein
- A, L, z, R1, n and B are defined as described above.
A photoradiolabelled compound comprising formula 5a, 5b, 5c, 5d or 5e,
- wherein
- A*, L, z, R1, n and B are defined as described above.
The compound according to any one of the preceding claims, wherein the chelator is selected from NODAGA, NOTA, DOTA, Desferrioxamine B (DFO), ATSM, DOTAGA, HBED-CC, SAAC, DTPA, DTPA-benzyl, DFO-Star, oxoDFO-Star, HOPO, p-SCN-Bn-HOPO
- and derivatives thereof, in particular from NODAGA, NOTA, Desferrioxamine B (DFO), ATSM, DOTAGA, HBED-CC, SAAC, DFO-Star, oxoDFO-Star, p-SCN-Bn-HOPO,
- and derivatives thereof.
The compound according to any one of the preceding claims, wherein L is a linker comprising one or more moieties, particularly 1 to 20 moieties, more particularly 1 to 15 moieties, selected from —C(═X)—, —NR6—, —C(═X)—NR6—, —NR6—C(═X)—, —NR6—C(═X)—NR6—, —O—C(═X)—NR6—, —NR6—C(═X)—O—, —O—, —C1-8-alkyl-, particularly selected from —C(═X)—, —NR6—, —C(═X)—NR6—, —NR6—C(═X)—, —NR6—C(═X)—NR6—, —O—, —C1-8-alkyl-,
- with R6 being H or C1-8-alkyl and X being O or S.
The compound according to any one of the preceding claims, wherein L is —C(═O)— or L comprises one or more moieties selected from —C(═X)—, —NR6—, —C(═X)—NR6—, —NR6—C(═X)—, —NR6—C(═X)—NR6—, —O—, —C1-8-alkyl- with R6 being H or C1-8-alkyl and X being O or S, wherein a moiety that comprises a heteroatom N, O or S alternates with an alkyl moiety, wherein in particular one or both ends of the linker are independently formed by a moiety that comprises a heteroatom N, O or S.
The compound according to any one of the preceding claims, wherein L is —C(═O)— or a moiety of formula 2,
- Ran—(C1-6-alkyl)-Rbm—Rc— (2), wherein
- Ra is —C(═O)—, —NR6—C(═X)—NR6—, or —NR6—, particularly —C(═O)— or —NR6—, more particularly —NR6—, with R6 being H or C1-4-alkyl, or Ra is a moiety —X1—C1-8-alkyl —X2— with X1 and X2 being a moiety independently selected from —C(═O)—, —NR6—, —C(═X)—NR6—, —NR6—C(═X)—, —NR6—C(═X)—NR6—, —O—C(═X)—NR6—, —NR6—C(═X)—O—, particularly —C(═O)—, —NR6—, —C(═O)—NR6—, —NR6—C(═O)—,
- n is 0 or 1,
- Rb is a polyether moiety with p elements [—O—Cu-alkyl], wherein u is independently selected for each element from an integer between 1 to 4 and p is an integer between 1 and 6,
- m is 0 or 1,
- Rc is —NR5—C(═O)—, —NR5—C(═X)—NR5—, —O—C(═X)—NR5—, —NR5—C(═X)—O—, wherein
- R5 is independently from each other H or C1-4-alkyl
- X is O or S, particularly S.
Dependencies are inferred from the claim text.