TUMOR-TARGETED OPTICAL CONTRAST AGENTS

• US 20080008655A1
• Filed: 03/05/2007
• Published: 01/10/2008
• Est. Priority Date: 01/18/2000
• Status: Active Grant

• Current Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Dorshow, Richard, Periasamy, Muthunadar, Rajagopalan, Raghavan, Achilefu, Samuel, Bugaj, Joseph
• Granted Patent: US 7,514,069 B2
• Time in Patent Office: Days
• US Class Current: 424/009.6
• CPC Class Codes: A61K 41/0033 Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds ultrasound therapy per se A61N7/00
• CPC Class Codes: A61K 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07K 1/13 Labelling of peptides
• CPC Class Codes: C07K 14/655 Somatostatins

Abstract

Cyanine dye bioconjugates useful for diagnostic imaging and therapy are disclosed. The conjugates include several cyanine dyes with a variety of bis- and tetrakis (carboxylic acid) homologs. The compounds may be conjugated to bioactive peptides, carbohydrates, hormones, drugs, or other bioactive agents. The small size of the compounds allows more favorable delivery to tumor cells as compared to larger molecular weight imaging agents. The various dyes are useful over the range of 350 to 1300 nm, the exact range being dependent upon the particular dye. The use of dimethylsulfoxide helps to maintain the fluorescence of the compounds. The inventive compounds are useful for diagnostic imaging and therapy, in endoscopic applications for the detection of tumors and other abnormalities, for localized therapy, for photoacoustic tumor imaging, detection and therapy, and for sonofluoresence tumor imaging, detection and therapy.

Claims

1. A compound of formula

2. The compound of claim 1 wherein each W⁴ and X⁴ is —

NR³;

Y⁴ is —

(CH₂)₂—

CONH-Bm;

Z⁴ is —

(CH₂)₂—

CONH-Dm;

A₂ is a single bond;

A₂, B₂, C₂, and D₂ together form a 6-membered carbocyclic ring;

each a₄ and b₄ is 1;

R⁴⁵ is galactose;

each R⁴⁶ to R⁵⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14)

3. The compound of claim 1 wherein each W⁴ and X⁴ is —

O—

;

Y⁴ is —

(CH₂)₂—

CONH-Bm;

Z⁴is —

(CH₂)₂—

CONH-Dm;

A₂ is a single bond;

A₂, B₂, C₂, and D₂ together form a 6-membered carbocyclic ring;

each a₄ and b₄ is 1;

R⁴⁵ is galactose;

each R⁴⁶ to R⁵⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14)

4. The compound of claim 1 wherein each W⁴ and X⁴ is —

Se;

Y⁴ is —

(CH₂)₂—

CONH-Bm;

Z⁴is —

(CH₂)₂—

CONH-Dm;

A₂ is a single bond;

A₂, B₂, C₂, and D₂ together form a 6-membered carbocyclic ring;

each a₄ and b₄ is 1;

R⁴⁵ is galactose;

each R⁴⁶ to R⁵⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14).

5. The compound of claim 1 wherein a porphyrin or a photodynamic therapy agent is attached to Bm, Dm, and combinations thereof.

6. A composition comprising a compound of formula

7. The composition of claim 6 wherein each of W⁴ and X⁴ is —

NR³;

Y⁴ is —

(CH₂)₂—

CONH-Bm;

Z⁴ is —

(CH₂)₂—

CONH-Dm;

A₂ is a single bond;

A₂, B₂, C₂, and D₂ together form a 6-membered carbocyclic ring;

a₄ and b₄ are independently galactose;

each of R⁴⁶ to R⁵⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14).

8. The composition of claim 6 wherein each of W⁴ and X⁴ is —

O—

;

Y⁴ is —

(CH₂)₂—

CONH-Bm;

Z⁴ is —

(CH₂)₂—

CONH-Dm;

A₂ is a single bond;

A₂, B₂, C₂, and D₂ together form a 6-membered carbocyclic ring;

a₄ and b₄ are independently galactose;

each of R⁴⁶ to R⁵⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14).

9. The composition of claim 6 wherein each of W⁴ and X⁴ is —

Se—

;

Y⁴ is —

(CH₂)₂—

CONH-Bm;

Z⁴ is —

(CH₂)₂—

CONH-Dm;

A₂ is a single bond;

A₂, B₂, C₂, and D₂ together form a 6-membered carbocyclic ring;

a₄ and b₄ are independently galactose;

each of R⁴⁶ to R⁵⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14).

10. The composition of claim 6 wherein Bm, Dm, and combinations thereof further comprise a porphyrin or a photodynamic therapy agent.

11. The composition of claim 6 further comprising a non-optical contrast agent.

12. A method for performing a diagnostic or therapeutic procedure comprising

administering to an individual an effective amount of the compound of formula

wherein W⁴ and X⁴ are independently selected from the group consisting of —

O—

, —

NR³, and —

Se—

;

Y⁴ is selected from the group consisting of —

(CH₂)_a—

CONH-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Bm, —

(CH₂)_a—

NHCO-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Bm, —

(CH₂)_a—

N(R³)—

(CH₂)_b—

CONH-Bm, (CH₂)_a—

N(R³)—

(CH₂)_c—

NHCO-Bm, —

(CH₂)_a—

N(R³)—

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Bm, —

(CH₂)_a—

N(R³)—

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

(CH₂)_a—

CONH-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

(CH₂)_a—

NHCO-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

CH₂—

(CH₂OCH₂)_d—

CONH-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

CH₂—

(CH₂OCH₂)_d—

NHCO-Bm, —

(CH₂)_a—

NR³R⁴, and —

CH₂(CH₂OCH₂)_b—

CH₂NR³R⁴;

Z⁴ is selected from the group consisting of —

(CH₂)_a—

CONH-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Dm, —

(CH₂)_a—

NHCO-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Dm, —

(CH₂)_a—

N(R³)—

(CH₂)_b—

CONH-Dm, —

(CH₂)_a—

N(R³)—

(CH₂)_c—

NHCO-Dm, —

(CH₂)_a—

N(R³)—

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Dm, —

(CH₂)_a—

N(R³)—

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

(CH₂)_a—

CONH-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

(CH₂)_a—

NHCO-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

CH₂—

(CH₂OCH₂)_d—

CONH-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

CH₂—

(CH₂OCH₂)_d—

NHCO-Dm, —

(CH₂)_a—

NR³R⁴, and —

CH₂(CH₂OCH₂)_b—

CH₂NR³R⁴;

A₂ is a single or a double bond;

B₂, C₂, and D₂ are independently selected from the group consisting of —

O—

, —

S—

, —

Se—

, —

P—

, —

CR¹R², —

CR¹, alkyl, NR³, and —

C═

O;

A₂, B₂, C₂, and D₂ may together form a 6- to 12-membered carbocyclic ring or a 6- to 12-membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom;

a₄ and b₄ are independently from 0 to 5;

R¹ to R⁴, and R⁴⁵ to R⁵⁷ are independently selected from the group consisting of hydrogen, C₁-C₁₀ alkyl, C₅-C₂₀ aryl, C₁-C₁₀ alkoxyl, C₁-C₁₀ polyalkoxyalkyl, C₁-C₂₀ polyhydroxyalkyl, C₅-C₂₀ polyhydroxyaryl, C₁-C₁₀ aminoalkyl, glucose derivatives of R groups, cyano, nitro, halogen, saccharide, peptide, —

CH₂(CH₂OCH₂)_b—

CH₂—

OH, —

(CH₂)_a—

CO₂H, —

(CH₂)_a—

CONH-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Bm, —

(CH₂)_a—

NHCO-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Bm, —

(CH₂)_a—

OH and —

CH₂—

(CH₂OCH₂)_b—

CO₂H;

Bm and Dm are independently selected from the group consisting of a bioactive peptide, a protein, a cell, an antibody, an antibody fragment, a saccharide, a glycopeptide, a peptidomimetic, a drug, a drug mimic, a hormone, a metal chelating agent, a radioactive or nonradioactive metal complex, and an echogenic agent;

a and c are independently from 1 to 20; and

b and d are independently from 1 to 100, and performing the diagnostic or therapeutic procedure

13. The method of claim 12 comprising administering to an individual an effective amount of the compound wherein each of W⁴ and X⁴ is —

NR³;

Y⁴ is —

(CH₂)₂—

CONH-Bm;

Z⁴ is —

(CH₂)₂—

CONH-Dm;

A₂ is a single bond;

A₂, B₂, C₂, and D₂ together form a 6-membered carbocyclic ring;

each a₄ and b₄ is 1;

R⁴⁵ is galactose;

each R⁴⁶ to R⁵⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14).

14. The method of claim 12 comprising administering to an individual an effective amount of the compound wherein each of W⁴ and X⁴ is —

O—

;

Y⁴ is —

(CH₂)₂—

CONH-Bm;

Z⁴ is —

(CH₂)₂—

CONH-Dm;

A₂ is a single bond;

A₂, B₂, C₂, and D₂ together form a 6-membered carbocyclic ring;

each a₄ and b₄ is 1;

R⁴⁵ is galactose;

each R⁴⁶ to R⁵⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14).

15. The method of claim 12 comprising administering to an individual an effective amount of the compound wherein each of W⁴ and X⁴ is —

Se—

;

Y⁴ is —

(CH₂)₂—

CONH-Bm;

Z⁴ is —

(CH₂)₂—

CONH-Dm;

A₂ is a single bond;

A₂, B₂, C₂, and D₂ together form a 6-membered carbocyclic ring;

each a₄ and b₄ is 1;

R⁴⁵ is galactose;

each R⁴⁶ to R⁵⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14).

16. The method of claim 12 wherein said procedure utilizes light of wavelength in the region of 350-1300 nm.

17. The method of claim 12 wherein said procedure further comprises imaging and therapy, wherein said imaging and therapy is selected from the group consisting of absorption, light scattering, photoacoustic and sonofluoresence technique.

18. The method of claim 12 further comprising attaching a compound selected from the group consisting of a porphyrin and a photodynamic therapy agent to Bm, Dm, and combinations thereof, and providing light of a wavelength sufficient to activate the porphyrin or phototherapy agent.

19. The method of claim 12 further comprising administering a non-optical contrast agent and imaging by at least one of magnetic resonance, ultrasound, X-ray, positron emission tomography, computed tomography, and single photon emission computed tomography.

20. The method of claim 12 wherein the compound is administered in a formulation selected from at least one of liposomes, micelles, microcapsules, or microparticles.