Heterodimers of Glutamic Acid

• US 20120269726A1
• Filed: 10/12/2011
• Published: 10/25/2012
• Est. Priority Date: 11/08/2006
• Status: Active Grant

• Current Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Original Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Inventors: Babich, John W., Zimmerman, Craig N., Maresca, Kevin P.
• Granted Patent: US 9,309,193 B2
• Time in Patent Office: Days
• US Class Current: 424/1.85
• CPC Class Codes: A61K 39/385 Haptens or antigens, bound to carriers
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 59/001 Acyclic or carbocyclic compounds
• CPC Class Codes: C07C 275/16 being further substituted by carboxyl groups
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 275/30 being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 311/19 to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom

Abstract

Compounds of Formula (Ia)

wherein R is a C₆-C₁₂ substituted or unsubstituted aryl, a C₆-C₁₂ substituted or unsubstituted heteroaryl, a C₁-C₆ substituted or unsubstituted alkyl or —NR′R′,
Q is C(O), O, NR′, S, S(O)₂, C(O)₂ (CH2)p
Y is C(O), O, NR′, S, S(O)₂, C(O)₂ (CH2)p
Z is H or C₁-C₄ alkyl,
R′ is H, C(O), S(O)₂, C(O)₂, a C₆-C₁₂ substituted or unsubstituted aryl, a C₆-C₁₂ substituted or unsubstituted heteroaryl or a C₁-C₆ substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C₁-C₁₂ heteroaryl, —NR′R′ or COOZ, which have diagnostic and therapeutic properties, such as the treatment and management of prostate cancer and other diseases related to NAALADase inhibition. Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.

Claims

1. A method of imaging one or more organs or tissues or both of a mammal comprising administering to a mammal an effective amount of a glutamate-urea-lysine PSMA-binding moiety conjugated to a radio-imaging moiety and obtaining an image of one or more organs or tissues or both of the mammal, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α

or β

-amino acid heterodimer coupled through the α

-NH₂ or β

-NH₂ groups.

2. The method of claim 1, wherein the one or more organs or tissues or both includes prostate tissue, kidney tissue, brain tissue, vascular tissue, or tumor tissue.

3. A kit comprising:

(i) compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a metal chelating moiety, and (ii) radionuclide.

4. The kit of claim 3, wherein the radionuclide is selected from technetium-99m, rhenium-186, rhenium-188 or combinations thereof.

5. A method of staging a pathological condition associated with one or more organs or tissues or both of a mammal comprising:

(i) administering to a mammal an effective amount of a compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a radio-imaging moiety, (ii) obtaining an image of the one or more organs or tissues or both of said mammal;

(iii) determining from said image the amount of PSMA which is present in the one or more organs or tissues or both of said mammal, and (iv) utilizing the amount determined and a control amount to arrive at a stage of the pathological condition, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α

or β

-amino acid heterodimer coupled through the α

-NH₂ or β

-NH₂ groups.

6. The method of claim 5, wherein the pathological condition is selected from the group consisting of cancer, prostate cancer, angiogenesis, heart failure, cardiomyopathy, lung disease, kidney dysfunction, renal failure, inflammation, atherosclerosis, vulnerable arterial plaques or neoplasm.

7. A method of monitoring a mammal'"'"'s response to therapy for a pathological condition associated with one or more organs or tissues or both of the mammal comprising (i) administering to a mammal an effective amount of a compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a radio-imaging moiety, (ii) obtaining an image of the one or more organs or tissues or both of the mammal, (iii) determining from said image the amount of peptidase which is present in the one or more organs or tissues or both of the mammal, and (iv) utilizing the amount determined and a control amount to gauge the mammal'"'"'s response, if any, to a therapy, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α

or β

-amino acid heterodimer coupled through the α

-NH₂ or β

-NH₂ groups.

8. The method of claim 7, wherein the control amount is obtained from an amount found in a group of normal subjects.

9. The method of claim 7, wherein the control amount is obtained from a baseline amount found in the one or more organs of said mammal.

10. A method of quantifying expression of a peptidase in one or more organs or tissues or both of a mammal comprising administering to a mammal an effective amount of a compound including a peptidase-binding moiety conjugated to a radio-imaging moiety, obtaining an image of the one or more organs or tissues or both of the mammal;

quantifying from the image and a series of standard images an amount of expression of the peptidase in the one or more organs or tissues or both of the mammal.

11. A method of treating a patient with painful and sensory diabetic neuropathy, neuronal damage and prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral schlerosis, or diabetic neuropathy comprising administering to the patient a therapeutically effective amount of a glutamate-urea-lysine PSMA-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α

or β

-amino acid heterodimer coupled through the α

-NH₂ or β

-NH₂ groups.

12. A method of treating a patient in need of an analgesic comprising administering to the patient a therapeutically effective amount of a glutamate-urea-lysine PSMA-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α

or β

-amino acid heterodimer coupled through the α

-NH₂ or β

-NH₂ groups.