Double-labeled probe for molecular imaging and use thereof

Patent metadata

Field	Value
Publication number	US-11638765-B2
Application number	US-201816765927-A
Country	US
Kind code	B2
Filing date	Nov 20, 2018
Priority date	Nov 21, 2017
Publication date	May 2, 2023
Grant date	May 2, 2023

Abstract

The present invention relates to a compound of a pharmaceutically acceptable salt thereof of formula (I) wherein (A) is at least one motif specifically binding to cell membranes of neoplastic cells; (B) at least one chelator moiety of radiometals; (C) a dye moiety; x1 is a spacer or a chemical single bond covalently connecting (A) to the rest of the molecule; x2 is a spacer or a chemical single bond covalently connecting (C) to the rest of the molecule. The invention further relates to compositions comprising said compounds as well as a method for detecting neoplastic cells in a sample in vitro with the aid of the compounds or composition.

First claim

The invention claimed is:

1. A compound or a pharmaceutically acceptable salt thereof of formula (I):

wherein
(A) is at least one moiety specifically binding to cell membranes of neoplastic cells;
(B) at least one chelator moiety of radiometals;
(C) a dye moiety;
x 1 is a spacer or a chemical single bond covalently connecting (A) to the rest of the molecule;
x 2 is a spacer or a chemical single bond covalently connecting (C) to the rest of the molecule;
wherein (C) has the formula

wherein
X 1 and X 4 are independently selected from the group consisting of —N═, —N(R 5 )═, and —C(R 6 )═;
X 2 and X 3 are independently selected from the group consisting of O, S, Se, N(R 5 ), and C(R 6 R 7 );
Y is a linker within (C) permitting electron delocalization within (C), wherein Y optionally comprises a group (L-) c Z 0 ;
a and b are independently selected from the group consisting of 1, 2, and 3;
each R 1 and each R 2 is independently (L-) c Z, (L-) c Z 0 or H; and two adjacent R 1 and/or two adjacent R 2 can also form an aromatic ring, which is optionally substituted with one or more (L-) c Z or (L-) c Z 0 ;
R 3 , R 4 , R 5 , R 6 , R 7 , R 9 are independently selected from the group consisting of (L-) c Z, (L-) c Z 0 , and H;
each c is independently 0, or 1;
each L is independently T 1 , —OT 1 -, —ST 1 -, —C(O)T 1 -, —C(O)OT 1 -, —OC(O)T 1 -, —C(O)NHT 1 -, —NHC(O)T 1 , or a C 1-10 alkylene group, which is optionally interrupted and/or terminated by one or more of —O—, —S—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)O—, and T 1 ;
T 1 is phenyl, naphthyl, indenyl, indanyl, tetralinyl, decalinyl, adamantyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclyl, or 7 to 11 membered heterobicyclyl, wherein T 1 is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, C(O)R 8 , COOR 8 , OR 8 , C(O)N(R 8 R 8a ), S(O) 2 N(R 8 R 8a ), S(O)N(R 8 R 8a ), S(O) 2 R 8 , N(R 8 )S(O) 2 N(R 8a R 8b ), SR 8 , N(R 8 R 8a ), NO 2 ; OC(O)R 8 , N(R 8 )C(O)R 8a , N(R 8 )S(O) 2 R 8a , N(R 8 )S(O)R 8a , N(R 8 )C(O)N(R 8a R 8b ), N(R 8 )C(O)OR 8a , OC(O)N(R 8 R 8a ), oxo (═O), wherein T 1 is at least partially saturated, or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
each Z is independently H, halogen, CN, C(O)R 8 , C(O)OR 8 , C(O)O − OR 8 , C(O)N(R 8 R 8a ), S(O) 2 OR 8 , S(O) 2 O − , S(O) 2 N(R 8 R 8a ), S(O)N(R 8 R 8a ), S(O) 2 R 8 , S(O)R 8 , N(R 8 )S(O) 2 N(R 8a R 8b ), SR 8 , N(R 8 R 8a ), NO 2 ; P(O)(OR 8 ) 2 , P(O)(OR 8 )O − , OC(O)R 8 , N(R 8 )C(O)R 8a , N(R 8 )S(O) 2 R 8a , N(R 8 )S(O)R 8a , N(R 8 )C(O)N(R 8a R 8b ), N(R 8 )C(O)OR 8a , or OC(O)N(R 8 R 8a );
R 8 , R 8a , R 8b are independently selected from the group consisting of H, or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
Z 0 is a chemical bond connecting (C) to x 2 or to the rest of the molecule in case x 2 is a chemical single bond;
provided that one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 is (L-) c Z 0 or that Y comprises (L-) c Z 0 ;

wherein c is 1 and L is C 3-7 alkylene;
wherein any remaining positive or negative charge or charges are compensated by pharmaceutically acceptable negatively or positively charged counterion or counterions.

2. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein said compound has a molecular weight of not more than 10 kDa.

3. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein the moiety specifically binding to cell membranes of neoplastic cells (A) is a moiety specifically binding to cell membranes of cancerous cells.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 3 , wherein the moiety specifically binding to cell membranes of neoplastic cells (A) is a PSMA binding moiety having the following structure:

wherein Z 1 , Z 2 and Z 3 are each independently from another selected from the group consisting of —C(O)OR 1a , —SO 2 R 1a , —SO 3 R 1a , —SO 4 R 1a , —PO 2 R 1a , —PO 3 R 1a , and —PO 4 R 1a R 2a , wherein R 1a and R 2a are independently from another H or a C 1-4 -alkyl residue;
wherein a′ represents a —[CH 2 ] o — residue, wherein o is an integer from 1 to 4,
wherein b′ represents a residue selected from the group consisting of —NH—, —C(O)— and —O—; and
wherein the wavy line indicates the conjugation site to the rest of the molecule.

5. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein the moiety specifically binding to cell membranes of neoplastic cells (A) is a PSMA binding moiety having the following structure:

wherein the wavy line indicates the conjugation site to the rest of the molecule.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the x 1 is a chemical single bond.

7. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein, in formula (I), (A) and x 1 are selected to give the following structure:

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein x 2 a chemical single bond.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the chelator moiety of radiometals (B) is derived from a chelator selected from:

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein, in formula (I), (A), x 1 and (B) are selected to give the following structure:

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein in formula (C) X 1 and X 4 are the same.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein in formula (C) X 2 and X 3 are the same.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein in formula (C) Y does not comprise (L-) c Z 0 .

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein in formula (C) a and b are the same.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein in formula (C) a and b are the same and 2.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein in formula (C) one of R 3 and R 4 is (L-) c Z 0 and the other is (L-) c Z with L-=C 1-10 alkylene and Z═H or SO 3 —.

17. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein (L-) c Z 0 is C 5 alkylene connecting (C) to x 2 or

Assignees

• Deutsches Krebsforsch
• Univ Heidelberg Ruprecht Karls
• Ruprecht Karls Uni Versitaet Heidelberg

Inventors

• Eder Matthias
• Kopka Klaus
• Schaefer Martin
• Bauder-Wuest Ulrike
• Haberkorn Uwe
• Eder Ann-Christin
• Cardinale Jens
• Benesova Martina

Classifications

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• C09B23/0025

  the substituent being bound through an oxygen atom · CPC title

• A61K49/106

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• G01N33/582

  with fluorescent label · CPC title