Metal complexes and fluorination thereof

Patent metadata

Field	Value
Publication number	US-11103604-B2
Application number	US-201414888908-A
Country	US
Kind code	B2
Filing date	May 2, 2014
Priority date	May 3, 2013
Publication date	Aug 31, 2021
Grant date	Aug 31, 2021

Abstract

A method of labelling biological molecules with 18 F, via attachment of fluorine to a metal complex, where the metal complex is conjugated to the biological molecule. The invention highlights the incorporation of hydrogen bonding (H-bonding) into the metal complex scaffold, and how this can be utilised to improve the kinetics of fluoride incorporation. Also provided are pharmaceutical compositions, kits and methods of in vivo imaging.

First claim

What is claimed is:

1. An imaging agent which comprises an 18 F-labelled compound of Formula I:

where:
X 1 , X 2 and X 3 are independently 19 F or 18 F, with the proviso that at least one of X 1 , X 2 and X 3 is 18 F;
M is Ga 3+ or In 3+ ;
Z 1 is a tridentate triamine chelating agent wherein all 3 amine donors are bound to M, wherein
Z 1 has at least one Y group, and optionally also a Q group covalently conjugated thereto;
p is 1, 2 or 3;
y is 0 or 1;
where Z 1 is of Formula Z a :

where each R 3 is independently H, C 1-4 alkyl, C 2-4 alkoxyalkyl, C 1-4 hydroxyalkyl, a Y group or a Q group;
each f is independently 1 or 2;
or Formula Z aa or Formula Z ab :

where R 4 is H, C 1-4 alkyl, C 2-4 alkoxyalkyl, C 1-4 hydroxyalkyl or a Y group;
R 5 is H, C 1-4 alkyl, C 2-4 alkoxyalkyl or C 1-4 hydroxyalkyl;
Y is independently -(A 1 ) x -Y 1 or -(A 1 ) x -Y 1 -Q where each A 1 is independently —CH 2 — or —O—;
wherein x is an integer of value 1 to 6; and
Y 1 is —NHR a , —NH(CH 2 ) 2 NHR a , —NH(CH 2 ) 3 NHR a , —(C═O)NHR a , —NH(C═O)R a , —NH(C═NH)NHR a , —OR a , R a , a Y 2 group or a Y 3 group;
Y 2 is:

Y 3 is Arg, Lys, Asn, Gln, Ser, Thr or Tyr;
wherein R a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 alkoxyalkyl, C 1-4 hydroxyalkyl, or -phenyl;
and wherein each R 1 is independently C 1-4 alkyl, C 2-4 alkoxyalkyl or C 1-4 hydroxyalkyl;
and R 2 is independently H, C 1-4 alkyl or Si(C 1-4 alkyl) 3 ;
Q is -L-[BTM];
L is a synthetic linker group of formula -(A) m - wherein each A is independently —CR 2 —, —CR═CR—, —C≡C—, —CO 2 CR 2 —, —NRCO—, —CONR—, —CR═N—O—, —NR(C═O)NR—, —NR(C═S)NR—, —SO 2 NR—, —NRSO 2 —, —CR 2 OCR 2 —, —CR 2 SCR 2 —, —CR 2 NRCR 2 —, a C 4-8 cycloheteroalkylene group, a C 4-8 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, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 alkoxyalkyl or C 1-4 hydroxyalkyl;
m is an integer of value 1 to 20;
each Ar is independently a C 5-12 arylene group, or a C 3-12 heteroarylene group;
BTM is a biological targeting moiety.

2. The imaging agent of claim 1 , where one Q group is present.

3. The imaging agent of claim 1 , where each Y group is covalently conjugated to a different amine donor atom of Z 1 .

4. The imaging agent of claim 1 , where the biological targeting moiety is chosen from: a single amino acid, a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist, an enzyme agonist, an enzyme inhibitor or a receptor-binding compound.

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

where:
X 1 , X 2 and X 3 are independently Br, Cl, 19 F or 18 F,
with the proviso that at least one of X′, X 2 and X 3 is 18 F;
M is Ga 3+ or In 3+ ;
Z 1 is a tridentate triamine chelating agent wherein all 3 amine donors are bound to M, wherein
Z 1 has at least one Y group, and optionally also a Q group covalently conjugated thereto;
p is 1, 2 or 3;
y is 0 or 1;
where Z 1 is of Formula Z a :

where each R 3 is independently H, C 1-4 alkyl, C 2-4 alkoxyalkyl, C 1-4 hydroxyalkyl, a Y group or a Q group;
each f is independently 1 or 2;
or Formula Z aa or Formula Z ab :

where R 4 is H, C 1-4 alkyl, C 2-4 alkoxyalkyl, C 1-4 hydroxyalkyl or a Y group;
R 5 is H, C 1-4 alkyl, C 2-4 alkoxyalkyl or C 1-4 hydroxyalkyl;
Y is independently -(A 1 ) x -Y 1 or -(A 1 ) x -Y 1 -Q where each A 1 is independently —CH 2 — or —O—;
wherein x is an integer of value 1 to 6; and
Y 1 is —NHR a , —NH(CH 2 ) 2 NHR a , —NH(CH 2 ) 3 NHR a , —(C═O)NHR a , —NH(C═O)R a , —NH(C═NH)NHR a , —OR a , R a , a Y 2 group or a Y 3 group;
Y 2 is:

Y 3 is Arg, Lys, Asn, Gln, Ser, Thr or Tyr;
wherein R a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 alkoxyalkyl, C 1-4 hydroxyalkyl, or -phenyl;
and wherein each R 1 is independently C 1-4 alkyl, C 2-4 alkoxyalkyl or C 1-4 hydroxyalkyl;
and R 2 is independently H, C 1-4 alkyl or Si(C 1-4 alkyl) 3 ;
Q is -L-[BTM];
L is a synthetic linker group of formula -(A) m - wherein each A is independently —CR 2 —, —CR═CR—, —C≡C—, —CO 2 CR 2 —, —NRCO—, —CONR—, —CR═N—O—, —NR(C═O)NR—, —NR(C═S)NR—, —SO 2 NR—, —NRSO 2 —, —CR 2 OCR 2 —, —CR 2 SCR 2 —, —CR 2 NRCR 2 —, a C 4-8 cycloheteroalkylene group, a C 4-8 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, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 alkoxyalkyl or C 1-4 hydroxyalkyl;
m is an integer of value 1 to 20;
each Ar is independently a C 5-12 arylene group, or a C 3-12 heteroarylene group;
BTM is a biological targeting moiety,
the method comprising, reacting a precursor with a supply of [ 18 F]-fluoride or [ 18 F]NaF, optionally in the presence of [ 19 F]-fluoride, in a suitable solvent to form the compound of Formula I,
wherein said precursor comprises a metal complex of a chelator of Formula II:

where Z 1 , Y, Q, p and q are as defined in Formula I;
and where said metal is chosen from: Ga 3+ or In 3+ .

6. The method of claim 5 , where said precursor is of Formula III:

where X 1a , X 2a and X 3a are independently Br or Cl.

7. The method of claim 6 , where X 1a =X 2a =X 3a ═Cl.

8. A radiopharmaceutical composition which comprises the imaging agent of claim 1 , together with a biocompatible carrier, in a form suitable for mammalian administration.

Assignees

• Ge Healthcare Ltd
• Univ Southampton
• Ge Healthcare Uk Ltd

Inventors

• Bhalla Rajiv
• Reid Gill
• Levason William

Classifications

• C07D255/02 Primary

  not condensed with other rings · CPC title

• C07F5/003

  without C-Metal linkages · CPC title

• A61K51/0482 Primary

  chelates from cyclic ligands, e.g. DOTA · CPC title