Metal complexes and fluorination thereof

A method of preparation of an imaging agent which comprises an 18F-labelled compound of Formula I:

• where:
• X1, X2 and X3 are independently Br, Cl, 19F or 18F, with the proviso that at least one of X1, X2 and X3 is 18F;
• M is Al3+, Ga3+, In3+, Sc3+, Y3+, Ho3+, Er3+, Tm3+, Yb3+ or Lu3+;
• Z1 is of Formula Za
• where each R3 is independently H, C1-4 alkyl, C2-4 alkoxyalkyl, C1-4 hydroxyalkyl, a Y group or a Q group;
• each f is independently 1;
• p is 1, 2 or 3;
• y is 0 or 1;
• Y is independently -(A′)x-Y1 or -(A′)x-Y1-Q where each A1 is independently —CH2— or —O—, provided that Y does not comprise any —O—O— bonds;
• wherein x is an integer of value 1 to 6;
• and
• Y1 is —NHRa, —NH(CH2)2NHRa, —NH(CH2)3NHRa, —(C═O)NHRa, —NH(C═O)Ra, —NH(C═NH)NHRa, —ORa or a Y3 group;
• Y3 is Arg, Lys, Asn, Gln, Ser, Thr or Tyr;
• wherein Ra is independently H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 alkoxyalkyl or C1-4 hydroxyalkyl;
• Q is -L-[BTM];
• L is a synthetic linker group of formula -(A)m- wherein each A is independently —CR2—, —CR═CR—, —C≡C—, —CR2CO2—, —CO2CR2—, —NRCO—, —CONR—, —CR═N—O—, —NR(C═O)NR—, —NR(C═S)NR—, —SO2NR—, —NRSO2—, —CR2OCR2—, —CR2SCR2—, —CR2NRCR2—, a C4-8 cycloheteroalkylene group, a C4-8 cycloalkylene group, —Ar—, —NR—Ar—, —O—Ar—, —Ar—(CO)—, 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, C2-4 alkoxyalkyl or C1-4 hydroxyalkyl;
• m is an integer of value 1 to 20;
• each Ar is independently a C5-12 arylene group, or a C3-12 heteroarylene group;
• BTM is a biological targeting moiety chosen from:
• a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist, an enzyme agonist, an enzyme inhibitor or a receptor-binding compound,
• wherein the method comprising reaction of a precursor with a supply of [18F]-fluoride or [18F]NaF, optionally in the presence of [19F]-fluoride, in a suitable solvent,
• wherein said precursor of Formula III comprises a metal complex of a chelator of Formula II:
• where Z1, Y, Q, p and q are as defined in Formula Za;
• where X1a, X2a and X3a are independently Br or Cl;
• and
• where said metal is chosen from:
• Al3+, Ga3+, In3+, Sc3+, Y3+, Ho3+, Er3+, Tm3+, Yb3+ or Lu3+.

A chelating agent for use in producing an imaging agent which comprises an 18F-labelled compound of Formula I:

• where:
• X1, X2 and X3 are independently Br, Cl, 19F or 18F, with the proviso that at least one of X1, X2 and X3 is 18F;
• M is Al3+, Ga3+, In3+, Sc3+, Y3+, Ho3+, Er3+, Tm3+, Yb3+ or Lu3+;
• Z1 is of Formula Za
• where each R3 is independently H, C1-4 alkyl, C2-4 alkoxyalkyl, C1-4 hydroxyalkyl, a Y group or a Q group;
• each f is independently 1;
• p is 1, 2 or 3;
• y is 0 or 1;
• Y is independently -(A1)x-Y1 or -(A1)x-Y1-Q where each A1 is independently —CH2— or —O—, provided that Y does not comprise any —O—O— bonds;
• wherein x is an integer of value 1 to 6;
• and
• Y1 is —NHRa, —NH(CH2)2NHRa, —NH(CH2)3NHRa, —(C═O)NHRa, —NH(C═O)Ra, —NH(C═NH)NHRa, —ORa or a Y3 group;
• Y3 is Arg, Lys, Asn, Gln, Ser, Thr or Tyr;
• wherein Ra is independently H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 alkoxyalkyl or C1-4 hydroxyalkyl;
• Q is -L-[BTM];
• L is a synthetic linker group of formula -(A)m- wherein each A is independently —CR2—, —CR═CR—, —C═C—, —CR2CO2—, —CO2CR2—, —NRCO—, —CONR—, —CR═N—O—, —NR(C═O)NR—, —NR(C═S)NR—, —SO2NR—, —NRSO2—, —CR2OCR2—, —CR2SCR2—, —CR2NRCR2—, a C4-8 cycloheteroalkylene group, a C4-8 cycloalkylene group, —Ar—, —NR—Ar—, —O—Ar—, —Ar—(CO)—, 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, C2-4 alkoxyalkyl or C1-4 hydroxyalkyl;
• m is an integer of value 1 to 20;
• each Ar is independently a C5-12 arylene group, or a C3-12 heteroarylene group;
• BTM is a biological targeting moiety chosen from:
• a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist, an enzyme agonist, an enzyme inhibitor or a receptor-binding compound,
• wherein the chelating agent of Formula IIA:
• and
• where Z1, Y, Q, p and q are as defined in Formula I.