Iodine radiolabelling method

A method of radioiodination of a biological targeting moiety, said method comprising:

• (i) provision of a compound of Formula (I):
• (ii) reaction of said compound of Formula (I) with a compound of Formula (IIa) or Formula (IIb):
• I*—Y1—N3 (IIa)
• I*—Y1—CH≡N+—O− (IIb)
• in the presence of a click cycloaddition catalyst, to give a conjugate of Formula (IIIa) or (IIIb) respectively:
• wherein:
• I* is a radioisotope of iodine suitable for in vivo imaging, chosen from 123I, 124I or 131I;
• L1 is a linker group which may be present or absent, wherein said linker group is of formula -(A)m- wherein each A is independently —CR2—, —CR═CR—, —C≡C—, —CR2CO2—, —CO2CR2—, —NRCO—, —CONR—, —NR(C═O)NR—, —NR(C═S)NR—, —SO2NR—, —NRSO2—, —CR2OCR2—, —CR2SCR2—, —CR2NRCR2—, a C4-8 cycloheteroalkylene group, a C4-8 cycloalkylene group, a C5-12 arylene group, or a C3-12 heteroarylene group, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block;
• wherein each R is independently chosen from:
• H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxyalkyl or C1-4 hydroxyalkyl;
• and m is an integer of value 1 to 20;
• Y1 is —Ar1— or —X1—;
• where —Ar1— is C3-10 arylene, and
• —X1— is —CH═CH—(CH2)n or —CH═CH—(Ar1)j—(CH2)n—
• where j is 0 or 1, and n is an integer of value 0 to 4,
• wherein when Y1 is —X1—, I* is attached to —CH═CH terminus of X1;
• BTM is the biological targeting moiety chosen from:
• a single amino acid, a 3-80 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound;
• and
• wherein the compound of Formula (IIa) or (IIb) is generated as follows:
• reaction of a precursor of either Formula (IVa) or Formula (IVb) respectively:
• Ra3Sn—Y1—N3 (IVa)
• KF3B—Y1—CH≡N+—O− (IVb)
• wherein Y1 is as defined above, and each Ra is independently C1-4 alkyl;
• with a supply of radioactive iodide ion in the presence of an oxidising agent, to give the compound of Formula (IIa) or (IIb) respectively.

A method of radioiodination of a biological targeting moiety, said method comprising:

• (i) provision of a compound of Formula (I):
• (ii) reaction of said compound of Formula (I) with a compound of Formula (IIa) or Formula (IIb):
• I*—Y1—N3 (IIa)
• I*—Y1—CH≡N+—O− (IIb)
• in the presence of a click cycloaddition catalyst, to give a conjugate of Formula (IIIa) or (IIIb) respectively:
• wherein:
• I* is a radioisotope of iodine suitable for in vivo imaging, chosen from 123I, 124I or 131I;
• L1 is a linker group which may be present or absent, wherein said linker group is of formula -(A)m- wherein each A is independently —CR2—, —CR═CR—, —C≡C—, —CR2CO2—, —CO2CR2—, —NRCO—, —CONR—, —NR(C═O)NR—, —NR(C═S)NR—, —SO2NR—, —NRSO2—, —CR2OCR2—, —CR2SCR2—, —CR2NRCR2—, a C4-8 cycloheteroalkylene group, a C4-8 cycloalkylene group, a C5-12 arylene group, or a C3-12 heteroarylene group, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block;
• wherein each R is independently chosen from:
• H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxyalkyl or C1-4 hydroxyalkyl;
• and m is an integer of value 1 to 20;
• Y1 is —Ar1— or —X1—;
• where —Ar1— is C3-10 arylene, and
• —X1— is —CH═CH—(CH2)n—(Ar1)j— or —CH═CH—(Ar1)j—(CH2)n—
• where j is 0 or 1, and n is an integer of value 0 to 4,
• wherein when Y1 is —X1—, I* is attached to —CH═CH terminus of X1;
• BTM is the biological targeting moiety chosen from:
• a single amino acid, a 3-80 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound;
• and
• which method is carried out in an aseptic manner, such that the product of Formula (IIa) or (IIIb) is obtained as a radiopharmaceutical composition.

A method of radioiodination of a biological targeting moiety, said method comprising:

• (i) provision of a compound of Formula (I):
• (ii) reaction of said compound of Formula (I) with a compound of Formula (IIa) or Formula (IIb):
• I*—Y1—N3 (IIa)
• I*—Y1—CH≡N+—O− (IIb)
• in the presence of a click cycloaddition catalyst, to give a conjugate of Formula (IIIa) or (IIIb) respectively:
• wherein:
• I* is a radioisotope of iodine suitable for in vivo imaging, chosen from 123I, 124I or 131I;
• L1 is a linker group which may be present or absent, wherein said linker group is of formula -(A)m- wherein each A is independently —CR2—, —CR═CR—, —C≡C—, —CR2CO2—, —CO2CR2—, —NRCO—, —CONR—, —NR(C═O)NR—, —NR(C═S)NR—, —SO2NR—, —NRSO2—, —CR2OCR2—, —CR2SCR2—, —CR2NRCR2—, a C4-8 cycloheteroalkylene group, a C4-8 cycloalkylene group, a C5-12 arylene group, or a C3-12 heteroarylene group, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block;
• wherein each R is independently chosen from:
• H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxyalkyl or C1-4 hydroxyalkyl;
• and m is an integer of value 1 to 20;
• Y1 is —Ar1— or —X1—;
• where —Ar1— is C3-10 arylene, and
• —X1— is —CH═CH—(CH2)j— or —CH═CH—(Ar1)j—(CH2)n—
• where j is 0 or 1, and n is an integer of value 0 to 4,
• wherein when Y1 is —X1—, I* is attached to —CH═CH terminus of X1;
• BTM is the biological targeting moiety chosen from:
• a single amino acid, a 3-80 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound;
• and
• which method is carried out using an automated synthesizer apparatus.

A radiopharmaceutical composition comprising an effective amount of a compound of Formula (IIIa) or (IIIb), together with a biocompatible carrier medium:

• wherein:
• I* is a radioisotope of iodine suitable for in vivo imaging, chosen from 123I, 124I or 131I;
• L1 is a linker group which may be present or absent, wherein said linker group is of formula -(A)m- wherein each A is independently —CR2—, —CR═CR—, —C≡C—, —CR2CO2—, —CO2CR2—, —NRCO—, —CONR—, —NR(C═O)NR—, —NR(C═S)NR—, —SO2NR—, —NRSO2—, —CR2OCR2—, —CR2SCR2—, —CR2NRCR2—, a C4-8 cycloheteroalkylene group, a C4-8 cycloalkylene group, a C5-12 arylene group, or a C3-12 heteroarylene group, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block;
• wherein each R is independently chosen from:
• H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxyalkyl or C1-4 hydroxyalkyl;
• and m is an integer of value 1 to 20;
• Y1 is —Ar1— or —X1—;
• where —Ar1— is C3-10 arylene, and
• —X1— is —CH═CH—(CH2)n—(Ar1)j— or —CH═CH—(Ar1)j—(CH2)n—
• where j is 0 or 1, and n is an integer of value 0 to 4,
• wherein when Y1 is —X1—, I* is attached to —CH═CH terminus of X1;
• BTM is the biological targeting moiety chosen from:
• a single amino acid, a 3-80 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound.