Cancer imaging and treatment

• US 8,628,750 B2
• Filed: 02/27/2007
• Issued: 01/14/2014
• Est. Priority Date: 02/27/2006
• Status: Expired due to Fees

• Current Assignee: Technische Universitat Munchen
• Original Assignee: Technische Universitat Munchen
• Inventors: Wester, Hans Jrgen, Koglin, Norman, Kessler, Horst, Demmer, Oliver, Anton, Martina, Schwaiger, Markus, Laufer, Burkhardt
• Primary Examiner(s): Jones, D L
• Application Number:
  US12/280,829
• Publication Number:
  US 20110027175A1
• Time in Patent Office: 2,513 Days
• Field of Search: 424/1.11, 424/1.65, 424/1.69, 424/1.81, 424/1.85, 424/1.89, 424/9.1, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 514/1, 514/1.1, 534/7, 534 10- 16, 530/300, 530/311, 530/317, 530/328
• US Class Current: 424/1.69
• CPC Class Codes: A61K 51/08 Peptides, e.g. proteins , carriers being peptides, polyamino acids, proteins
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

Provided herein are compounds or conjugates useful for diagnostic imaging and/or therapeutic purposes. Each compound or conjugate comprises a ligand for the chemokine receptor CXCR4 and a detectable label. The ligand has a binding affinity for the CXCR4 receptor, measured as IC₅₀ in the presence of ¹²⁵I-CPCR4, of 250 nM or lower, and the ligand comprises a cyclic oligopeptide moiety having the motif B-Arg or B-(Me)Arg within the cyclic moiety, wherein B is a basic amino acid, a derivative thereof, or phenylalanine, provided that the motif is B-Arg when B is a N^α-methyl derivative of a basic amino acid.

Claims

1. A compound or conjugate, or a pharmaceutically acceptable salt or ester thereof, comprising a ligand for the chemokine receptor CXCR4 and a detectable label, the ligand having a binding affinity for the CXCR4 receptor, measured as IC₅₀ in the presence of ¹²⁵I-CPCR4, of 250 nM or lower, wherein the ligand comprises a cyclic oligopeptide moiety, wherein the cyclic oligopeptide moiety is:

2. A compound or conjugate according to claim 1 wherein Z is selected from the group consisting of Nal, (N-fluoropropionyl)-diaminopropionic acid (Dap(FB)) and an oxime of aminooxy serine and 4-flurobenzaldehvde (AMS(FB)).

3. A compound or conjugate according to claim 1 wherein B is N^α

-substituted with a Me group.

4. A compound or conjugate according to claim 1 wherein B is substituted Orn, the ornithine residue is substituted at N^δ

with one or two groups selected from fluorobenzoyl (FB), fluoropropionyl (FP), acetyl (Ac), amido (Am), Me, 1-naphthylmethyl (N1), 2-naphthylmethyl (N2), benzyl (Bz) and acyl spacer moieties, wherein the acyl spacer moiety is an acyl group containing a chain of 1-14 carbons, optionally interrupted by heteroatoms, and having a nucleophilic functional group at its end distal to the ornithine N^δ

;

or the ornithine residue is substituted at N^α

with a Me group.

5. A compound or conjugate according to claim 4 wherein the acyl spacer moiety is selected from aminohexanoyl (Ahx), triethyleneglycolamino acyl (TGAS), (Ahx)₂, (Ahx)₃, (TGAS)₂ and (TGAS)₃.

6. A compound or conjugate according to claim 1 wherein B is Orn substituted at N^δ

with FB, FP, Ac, Am, N1, N2, Me and N1, Me and N2, Bz, Bz and FB, Bz and FP, Me and FB, Me and FP, and optionally substituted at N^α

or N^δ

with a Me group.

7. A compound or conjugate according to claim 1, wherein the cyclic oligopeptide moiety has the sequence:

cyclo[D-Tyr-B-Arg-Z-X], wherein B, Z and X are as defined in claim 2, provided that not more than one of the residues in the said sequence is N^α

-methylated.

8. A compound or conjugate according to claim 1, wherein B is selected from Arg, (Me)Arg, Orn, Cit, Orn(FB), Orn(FP), Orn(Ac), Orn(Am), Orn(N1), Orn(N2), Orn(Me, N1), Orn(Me, N2), Orn(Me), Orn(Bz), Orn(Bz,FB), Orn(Ahx), Orn(Ahx₂), Orn(Ahx₃), Orn(TGAS), Orn(TGAS₂), Orn(TGAS₃), Orn(Me, FB), D-Orn(FB), (Me)D-Orn(FB), (Me)D-Orn(Me,FB), His and Phe, provided that not more than one of the residues in the said sequence is N^α

-methylated.

9. A compound or conjugate according to claim 1, wherein the first residue is D-Tyr, the third residue is Arg, Z is Nal, and X is Gly.

10. A compound or conjugate according to claim 1, wherein the cyclic oligopeptide moiety has a sequence selected from the group consisting of

11. A compound or conjugate according to claim 10, wherein the cyclic oligopeptide moiety has a sequence selected from the group consisting of

12. A compound or conjugate according to claim 11 wherein the cyclic oligopeptide moiety has a sequence selected from

13. A compound or conjugate according to claim 1, wherein the label is a radiolabel selected from ¹⁸F, ⁴⁷Sc, ⁵¹Cr, ⁵²Fe, ^52mMn, ⁵⁶Ni, ⁵⁷Ni, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, ⁶⁸Ga, ⁷²As, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁸²Br, ⁸⁹Zr, ^94mTc, ⁹⁷Ru, ^99mTc, ¹¹¹In, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁹¹Pt, ¹⁹⁷Hg, ²⁰¹Tl, ²⁰³Pb, ^110mIn, ¹²⁰I.

14. A compound or conjugate according to claim 1 wherein the compound has a ¹⁸F label present on an FB or FP substituent at N^δ

of Orn or D-Orn.

15. A compound or conjugate according to claim 1 wherein the conjugate has a radiolabel which is attached to the ligand by conjugation of an organic complexation agent and a radionuclide.

16. A compound or conjugate according to claim 15, wherein the complexation agent is attached to the ligand through a spacer group.

17. A compound or conjugate according to claim 1, wherein the label is a radiolabel selected from the group consisting of ³²P, ⁶⁷Cu, ⁷⁷As, ⁹⁰Y, ⁹⁹Mo, ¹⁰³Ru, ¹⁰⁵Rh, ¹⁰⁹Pd, ¹¹¹Ag, ^114mIn, ^117mSn, ¹²¹Sn, ¹²⁷Te, ¹³¹I, ¹⁴⁰La, ¹⁴⁰Nd, ¹⁴²Pr, ¹⁴³Pr, ¹⁴⁹Tb, ¹⁴⁹Pm, ¹⁵¹Pm, ¹⁵³Sm, ¹⁵⁹Gd, ¹⁶¹Tb, ¹⁶⁶Ho, ¹⁶⁶Dy, ¹⁶⁹Er, ¹⁶⁹Yb, ¹⁷²Tm, ¹⁷⁵Yb, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁹⁸Au, ¹⁹⁹Au, ²¹¹At, ²¹¹Bi, ²¹²Bi, ²¹³Bi, ²²⁵Ac.

18. A method of imaging neoplastic tissue, the method comprising administering to a subject having or suspected of having a neoplasia, a compound or conjugate of claim 1, and detecting the compound following distribution thereof in vivo by imaging the subject.

19. A method according to claim 18 wherein the imaging is performed using PET or SPECT when the label is a radionuclide.