Methods for low temperature fluorine-18 radiolabeling of biomolecules

Patent metadata

Field	Value
Publication number	US-11420910-B2
Application number	US-201515522859-A
Country	US
Kind code	B2
Filing date	Oct 29, 2015
Priority date	Oct 30, 2014
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

Abstract

New chelators such as H3L1, H3L2, H3L3, H3L26 and derivatives were synthesized for the complexation of {Al18F}2+. These new chelators are able to complex {AI18F}2+ with good radiochemical yields using a labeling temperature of 37° C. The stability of the new Al18F-complexes was tested in phosphate buffered saline (PBS) at pH 7 and in rat serum. AI18F-L3 and AI18F-L26 showed a stability comparable to that of the previously reported Al18F-NODA. Moreover, the biodistribution of Al18F-L3 and AI18F-L26 showed absence of in vivo demetallation since only very limited bone uptake was observed, whereas the major fraction of activity 60 min p.i. was observed in liver and intestine due to hepatobiliary clearance of the radiolabeled ligand. The chelators H3L3 and Al18F-L26 demonstrated to be a good lead candidates for the labeling of heat sensitive biomolecules with 18F-fluorine and derivatives have been synthesized. We have explored the complexation of {AI18F}2+ with new chelators and obtained very favourable radiochemical yields (>85%) using a labeling temperature of 37° C. The stability of the new Al18F-complexes was tested in phosphate buffered saline (PBS) at pH 7 and in rat serum at 37° C., where AI18F-L3 and AI18F-L26 showed a stability comparable to that of the previously reported Al18F-NODA. Moreover, the biodistribution of Al18F-L3 and Al18F-L26 showed high stability, since only very limited bone uptake—which would be an indication of release of fluorine-18 in the form of fluoride—was observed, whereas the major fraction of activity 60 min p.i. was observed in liver and intestines due to hepatobiliary clearance of the radiolabeled ligand. The chelators H3L3 and H3L26 demonstrated to be good lead candidates for the labeling of heat sensitive biomolecules with 18F-fluorine and several derivatives have been synthesized.

First claim

The invention claimed is:

1. A chelate of {Al 18 F} 2+ with a compound selected from the group consisting of:
a compound having the formula (I):

wherein:
n2 is 4, wherein the 6-membered ring is cyclic without additional substituents, or includes a double bond, or is aromatic;
Z is OH;
R 7 is a —CH 2 -Ph-R′ group with R′ in ortho, meta or para position, wherein R′ is selected from the group consisting of a hydrogen atom, —COOH, —NH 2 , —N═C═S, —SH, an activated ester and a group bearing a maleimide adapted to couple with compounds bearing a suitable chemical function,
the asymmetric carbon atoms are in (R) or (S) configuration,
or a pharmaceutically acceptable salt thereof.

2. A kit for radiolabeling of a molecule with 18 F, including a heat sensitive molecule, whereby the kit comprises an {Al 18 F} 2+ chelate according to claim 1 , wherein the heat sensitive molecule is a peptide or a protein.

3. The kit according to claim 2 , whereby the kit further comprises reagents or media.

4. The chelate of claim 1 , wherein the chelate is obtained at a temperature <40° C.

Assignees

• Univ Leuven Kath

Inventors

• Musthakahmed Ahamed Muneer Syed
• Billaud Emilie
• Bormans Guy
• CLEEREN Frederik
• LECINA Joan
• Verbruggen Alfons

Classifications

• C07C229/38

  having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton · CPC title

• C07C331/28

  having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings · CPC title

• A61K51/1093

  conjugates with carriers being antibodies · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07D243/08

  not condensed with other rings · CPC title