Dendrimer precursor dyes for imaging

• US 6,395,257 B1
• Filed: 01/18/2000
• Issued: 05/28/2002
• Est. Priority Date: 01/18/2000
• Status: Expired due to Term

• Current Assignee: MediBeacon Inc.
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Rajagopalan, Raghavan, Dorshow, Richard B., Achilefu, Samuel, Bugaj, Joseph E.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/484,322
• Time in Patent Office: 861 Days
• Field of Search: 424/9.6,9.1,1.1,1.65 540/484,553,554 514/411 548/120,150,219,302.1,427
• US Class Current: 424/9.6
• 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 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• 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: C09B 23/0066 the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
• CPC Class Codes: C09B 23/08 more than three >CH- groups, e.g. polycarbocyanines

Abstract

The sensitivity and specificity of the optical modality can be enhanced by the use of highly absorbing dyes as contrast agents. Novel cyanine dyes that absorb and emit light in the near infrared region of electromagnetic spectrum are disclosed. These dyes are useful for imaging, diagnosis and therapy of various diseased states. Particularly, the molecules of the invention are useful for optical 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 sonofluorescence tumor imaging, detection and therapy.

Claims

1. A method for performing a diagnostic or therapeutic procedure which comprises administering to an individual an effective amount of the composition of an indocyanine dye of the formula

wherein a₆ varies from 0 to 5;

W⁶ and X⁶ may be the same or different and are selected from the group consisting of —

CR¹⁰R¹¹, —

O—

, —

NR¹², —

S—

, and —

Se;

Y⁶ and Z⁶ may be the same or different and are selected from the group consisting of —

(CH₂)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_d—

CH₂—

CO₂H, —

(CH₂)_e—

NH₂, —

CH₂—

(CH₂—

OCH₂)_fCH₂NH₂, (CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H, and —

(CH₂)_i—

N(R¹⁵)—

CH₂—

(CH₂—

O—

CH₂)_j—

CH₂—

CO₂H;

A₄ is a single or a double bond;

if A, is a single bond, then B₄ and C₄ may the same or different and are selected from the group consisting of —

O—

, —

S, —

Se—

, —

P— and

—

NR³⁸ and D₄ is selected from —

CR³⁹R⁴⁰ and —

C═

O;

if A₄ is a double bond, then B₄ is selected from the group consisting of —

O—

, —

S—

, —

Se—

, —

P— and

—

NR³⁸, C₄ is selected from nitrogen and —

CR⁴¹ and D is —

CR⁴², R⁶⁷ to R⁷⁹ may be the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, hydrophilic peptide, C1-C10 aryl, hydroxyl, C1-C10 polyhydroxyalkyl, C1-C10 alkoxyl, cyano, nitro, halogen, and —

NR⁴³R⁴⁴, R¹⁰ to R¹², R¹⁴ and R¹⁵ may be the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 aryl, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, —

CH₂(CH—

O—

CH₂)_c—

CH₂—

OH, C1-C20 polyhydroxyalkyl, C1-C10 polyhydroxyaryl, —

(CH₂)_dCO₂H, —

CH₂—

(CH₂—

O—

CH₂)_e—

CH₂—

CO₂H, —

(CH₂)_fNH₂ and —

CH—

(CH₂—

O—

CH₂)_g—

CH₂NH₂, R³⁸ to R⁴² may be same or different and are selected from the group consisting of -hydrogen, C1-C10 alkyl, C1-C10 aryl, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, —

CH₂(CH—

O—

CH₂)_c—

CH₂—

OH, C1-C20 polyhydroxyalkyl, C1-C10 polyhydroxyaryl, —

(CH₂)_dCO₂H, CH₂(CH₂—

O—

CH₂)_e—

CH₂—

CO₂H, —

(CH₂)_fNH₂, and —

CH₂—

(CH₂—

O—

CH₂)_g—

CH₂—

NH₂;

c, e, g, h, and i vary from 1 to 10;

d, f and j vary from 1 to 100; and

R⁴³ and R⁴⁴ may be the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, and C1-C10 aryl, or may together form a 5, 6, or 7 membered carbocyclic ring or a 5, 6, or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atoms, said composition in a pharmaceutically suitable carrier.

3. The method of performing the diagnostic or therapeutic procedure of claim 1 which comprises administering to an individual an effective amount of the composition of indocyanine dye wherein a₆ is 1;

A₄ is a double bond;

B₄ is —

O—

;

C₄and D₄ are CH;

R⁶⁷ is selected from the group consisting of hydrogen, a saccharide and a hydrophilic peptide;

R⁶⁸ to R⁷⁹ are hydrogens;

W⁶ and X⁶ may be the same or different and are selected from the group consisting of —

C((CH₂)_zzOH)CH₃, C((CH₂)_zzCO₂H)₂ and C((CH₂)_zzNR_ppR_pz)₂;

Y⁶ and Z⁶ are the same and are selected from the group consisting of —

(CH₂)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_d—

CH₂—

CO₂H, and —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H.

4. The method of claim 1 wherein said procedure utilizes light of wavelength in the region of 350-1300 nm.

5. The method of claim 1 wherein said diagnostic procedure is optical tomography.

6. The method of claim 1 wherein said diagnostic procedure is fluorescence endoscopy.

7. The method of claim 1 further comprising monitoring a blood clearance profile of said dye by fluorescence, absorbance or light scattering wherein light of wavelength in the region of 350-1300 nm is utilized.

8. The method of claim 1 wherein said procedure further comprises a step of imaging and therapy wherein said imaging and therapy is selected from the group consisting of absorption, light scattering, photoacoustic, and sonofluoresence technique.

9. The method of claim 1 wherein said procedure is for diagnosing atherosclerotic plaques and blood clots.

10. The method of claim 1 wherein said procedure further comprises administering localized therapy.

11. The method of claim 1 wherein said therapeutic procedure comprises photodynamic therapy.

12. The method of claim 1 wherein said therapeutic procedure comprises laser assisted guided surgery (LAGS) for the detection of micrometastases.

2. The method of performing the diagnostic or therapeutic procedure which comprises administering to an individual an effective amount of a composition of indocyanine dye of the formula

wherein a₆ varies from 0 to 3;

A₄ is a single bond;

B₄ is selected from the group consisting of —

O—

, —

S—

, and —

NR³⁸;

D₄ is selected from —

CH₂ and —

C═

O;

C₄ is selected from the group consisting of —

O—

, —

S—

, and —

NR³⁸;

R⁶⁷ is selected from the group consisting of hydrogen, a halogen atom, a saccharide and a hydrophilic peptide;

R⁶⁸ to R⁷⁹ are hydrogens;

W⁶ and X⁶ may be the same or different and are selected from the group consisting of —

C(CH₃)₂, C((CH₂)_zzOH)CH₃, C((CH₂)_zzOH)₂, C((CH₂)_zzCO₂H)CH₃, C((CH₂)_zzCO₂H)₂, C((CH₂)_zzNH₂)CH₃, C((CH)_zzNH₂)₂, C((CH₂)_zzNR_ppR_pz)CH₃ and C((CH₂)_zzNR_ppR_pz)₂;

Y⁶ and Z⁶ may be the same or different and are selected from the group consisting of —

(CH₂)_c—

CO₂H, —

CH—

(CH₂—

O—

CH₂)_d—

CH₂—

CO₂H, —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H and —

(CH₂)_i—

N(R¹⁵)—

CH₂—

(CH₂—

O—

CH₂)_j—

CH₂—

CO₂H;

R_pp and R_pz are the same or different and are selected from —

(CH₂)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_d—

CH₂—

CO₂H, —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H, or —

CH₂)_i—

N(R¹⁵)—

CH₂—

(CH₂—

O—

CH₂)_jCH₂—

CO₂H;

c, e, g, h, i and zz vary from 1 to 5;

d, f and j vary from 1 to 100; and

R¹⁴ and R¹⁵ may be same or different and are selected from the group consisting of hydrogen C1-C10 alkyl, C1-C10 aryl, C1-C10 alkoxyl, C1-C10 polyalkoxcyalkyl, —

CH₂(CH₂—

O—

CH₂)_c—

CH₂—

OH, C1-C20 polyhydroxyalkyl, C1-C10 polyhydroxyaryl, —

(CH₂)_d—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_e—

CH₂—

CO₂H, —

(CH₂)_f—

NH₂, and —

CH₂—

(CH₂—

O—

CH₂)_g—

CH₂—

NH₂, said composition in a pharmaceutically acceptable carrier.