Tumor-targeted optical contrast agents

• US 6,641,798 B2
• Filed: 05/23/2001
• Issued: 11/04/2003
• 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., Bugaj, Joseph E., Achilefu, Samuel I.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/863,971
• Publication Number:
  US 20020044909A1
• Time in Patent Office: 895 Days
• Field of Search: 424/1.11, 424/1.65, 424/9.1, 424/9.6, 424/9.3, 424/9.4, 424/9.5, 548/400, 548/427, 548/416
• 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: A61P 35/00 Antineoplastic agents

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) homologes. 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 1,300 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 sonofluorescence tumor imaging, detection and therapy.

Claims

1. A compound of formula

wherein W⁴ and X⁴ are —

CR¹R²;

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—

CH₂CONH—

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, O₂, 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, 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.

2. The compound of claim 1 wherein W₄ and X₄ are independently selected from the group consisting of —

C(CH₃)₂, —

C((CH₂)_aOH)CH₃, —

C((CH₂)_aOH)₂, —

C((CH₂)_aCO₂H)CH₃, —

C((CH₂)_aCO₂H)₂, —

C((CH₂)_aNH₂)CH₃, C((CH₂)_aNH₂)₂, and C((CH₂)_aNR³R⁴)₂;

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—

NR³R⁴, and —

CH₂(CH₂OCH₃)_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—

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—

, NR³, (CH2)_a—

CR¹R², and —

CR¹;

A², B², C², and D² may together form a 6- to 10-membered carbocyclic ring or a 6- to 10-membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom;

a₄ and b₄ are independently from 0 to 3;

R¹ to R⁴, and R⁴⁵ to R⁵⁷ are independently selected from the group consisting of hydrogen, C₁-C₁₀ alkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkoxyl, C₁-C₁₀ polyhydroxyalkyl, C₅-C₁₂ polyhydroxyaryl, C₁-C₁₀ aminoalkyl, mono- or oligosaccharide, peptide with 2 to 30 amino acid units, —

CH₂(CH₂OCH₂)_b—

CH₂—

OH, —

(CH₂)_a—

CO₂H, —

(CH₂)_a—

CONH—

Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH—

Bm, —

(OH₂)₂—

NHCO—

Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO—

Bm, —

(CH₂)_aOH and —

CH₂—

(CH₂OCH₂)_b—

CO₂H;

Bm and Dm are independently selected from the group consisting of a bioactive peptide containing 2 to 30 amino acid units, an antibody, a mono- or oligosaccharide, a glycopeptide, a metal chelating agent, a radioactive or nonradioactive metal complex, and an echogenic agent;

a and c are independently from 1 to 10; and

b and d are independently from 1 to 30.

3. The compound of claim 2 wherein each W⁴ and X⁴ is C((CH₂)OH)₂;

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;

Dm is bombesin (7-14).

4. 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 —

CR¹R²;

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—

NHCO—

Bm, CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

(CH₂)—

CONH—

Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

(CH₂)—

NHCO—

Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

N(R³)—

CH₂—

(CH₂OCH₃)_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)₂—

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—

(OH₂OCH₂)_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, cyano, nitro, halogen, saccharide, peptide, —

CH₂(CH₂OCH₂)_b—

CH₂—

OH, —

(CH₂)_a—

CO₂H, —

(CH₂)₂CONH—

Bm, —

CH₂—

(OH₂OCH₂)_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,

activating the compound using light, and

performing the diagnostic or therapeutic procedure.

5. The method of claim 4 comprising administering to an individual an effective amount of the compound wherein W⁴ and X⁴ are independently selected from the group consisting of —

C(CH₃)₂, —

C((CH₂)_aOH)CH₃, —

C((CH₂)_aOH)₂, —

C((CH₂)_aCO₂H)CH₃, —

C((CH₂)_aCO₂H)₂, —

C((CH₂)_aNH₂)CH₃, C((CH₂)_aNH₂)₂, and C((CH₂)_aNR³R⁴)₂;

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—

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)_aNHCO—

Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO—

Dm, —

(CH₂)_aNR³R⁴, 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—

, NR³, (CH2)₂—

CR¹R², and —

CR¹;

A₂, B₂, C₂, and D₂ may together form a 6- to 10-membered carbocyclic ring or a 6- to 10-membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom;

a₄ and b₄ are independently from 0 to 3;

R¹ to R⁴, and R⁴⁵ to R⁵⁷ are independently selected from the group consisting of hydrogen, C₁-C₁₀ alkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkoxyl, C₁-C₁₀ polyhydroxyalkyl, C₅-C₁₂ polyhydroxyaryl, C₁-C₁₀ aminoalkyl, mono- or oligosaccharide, peptide with 2 to 30 amino acid units, —

CH₂(CH₂OCH₂)_b—

CH₂—

OH, —

(CH₂)_a—

CO₂H, —

(CH₂)_a—

CONH—

Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH—

Bm, —

(CH₂)_aNHCO—

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 containing 2 to 30 amino acid units, an antibody, a mono- or oligosaccharide, a glycopeptide, a metal chelating agent, a radioactive or nonradioactive metal complex, and an echogenic agent;

a and c are independently from 1 to 10; and

b and d are independently from 1 to 30.

6. The method of claim 5 comprising administering to an individual an effective amount of the compound wherein each of W⁴ and X⁴ is C((CH₂)OH)₂;

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;

Dm is bombesin (7-14).

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

8. The method of claim 4 wherein the diagnostic procedure is optical tomography.

9. The method of claim 4 wherein said diagnostic procedure is fluorescence endoscopy.

10. The method of claim 4 further comprising monitoring a blood clearance profile of said compound by a method selected from the group consisting of fluorescence, absorbance, and light scattering, wherein light of wavelength in the region of 350-1300 nm is used.

11. The method of claim 4 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.

12. The method of claim 4 wherein said procedure is capable of diagnosing atherosclerotic plaques and blood clots.

13. The method of claim 4 wherein said procedure comprises administering localized therapy.

14. The method of claim 4 wherein said therapeutic procedure comprises photodynamic therapy.

15. The method of claim 4 wherein said therapeutic procedure comprises laser assisted guided surgery for the detection of micrometastases.

16. The method of claim 4 further comprising adding a biocompatible organic solvent at a concentration of one to fifty percent to the compound to prevent in vivo or in vitro fluorescence quenching.

17. The method of claim 16 wherein said compound is dissolved in a medium comprising one to fifty percent dimethyl sulfoxide.

18. A composition comprising a cyanine dye bioconjugate of formula

wherein W⁴ and X⁴ are —

CR¹R²;

Y⁴ is selected from the group consisting of —

(CH₂)_a—

CONH—

Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH—

Bm, —

(CH₂)_a—

NHCO—

Bm, —

OH₂—

(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)_aNHCO—

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)_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)_a—

(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, 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 vary from 1 to 100, and a pharmaceutically acceptable carrier or excipient.

19. The composition of claim 18 wherein W⁴ and X⁴ are independently selected from the group consisting of —

C(CH₃)₂, —

C((CH₂)_aOH)CH₃, C((CH₂)_aOH)₂, —

C((CH₂)_aCO₂H)CH₃, —

C((CH₂)_aCO₂H)₂, —

C((CH₂)_aNH₂)CH₃, C((CH₂)_aNH₂)₂, and C((CH₂)_aNR³R⁴)₂;

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—

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, —

OH₂—

(CH₂OCH₂)_b—

CH₂—

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—

, NR³, (CH₂)_a—

CR¹R², and —

CR¹;

A₂, B₂, C₂, and D₂ may together form a 6- to 10-membered carbocyclic ring or a 6- to 10-membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom;

a₄ and b₄ are independently from 0 to 3;

R¹ to R⁴, and R⁴⁵ to R⁵⁷ are independently selected from the group consisting of hydrogen, C₁-C₁₀ alkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkoxyl, C₁-C₁₀ polyhydroxyalkyl, C₅-C₁₂ polyhydroxyaryl, C₁-C₁₀ aminoalkyl, mono- or oligosaccharide, peptide with 2 to 30 amino acid units, —

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 containing 2 to 30 amino acid units, an antibody, a mono- or oligosaccharide, a glycopeptide, a metal chelating agent, a radioactive or nonradioactive metal complex, and an echogenic agent;

a and c are independently from 1 to 10; and

b and d are independently from 1 to 30.

20. The composition of claim 19 wherein each of W⁴ and X⁴ is C((CH₂)OH)₂;

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).