Technetium- and rhenium-bis(heteroaryl) complexes, and methods of use thereof
One aspect of the invention relates to complexes of technetium (Tc) and rhenium (Re) with various heteroaromatic ligands, e.g., quinolinyl and isoquinolinyl ligands, and their use in fluorescence and radioimaging for a variety of clinical diagnostic applications, as well as radiopharmaceuticals for therapeutic applications. Another aspect of the invention relates to quinolinyl and isoquinolinyl ligands that form a portion of the aforementioned complexes. Methods for the preparation of the technetium and rhenium complexes are also described. Another aspect of the invention relates to quinolinyl and isoquinolinyl ligands based on derivatized lysine, alanine and bis-amino acids for conjugation to small peptides by solid phase synthetic methods. Additionally, the invention relates to methods for imaging regions of a mammal using the complexes of the invention.
1 - 25 . (canceled)
26 . A compound represented by C:
wherein
R is H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, aminoacyl, hydroxyacyl, thioacyl, —CO 2 H, —(CH 2 ) d —R 80 , or an amino acid radical;
R 80 is independently for each occurrence carboxaldehyde, carboxylate, carboxamido, alkoxycarbonyl, aryloxycarbonyl, ammonium, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, polycyclyl, amino acid, peptide, saccharide, ribonucleic acid, (deoxy)ribonucleic acid, or a ligand for a G-protein-coupled receptor;
d is an integer in the range 0 to 12 inclusive;
m is an integer in the range 0 to 6 inclusive;
n is an integer in the range 0 to 6 inclusive;
Z is thioalkyl, carboxylate, 2-(carboxy)aryl, 2-(carboxy)heteroaryl, 2-(hydroxy)aryl, 2-(hydroxy)heteroaryl, 2-(thiol)aryl, or 2-(thiol)heteroaryl; and
L is selected from the group consisting of
each instance of R 1 is selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, acyl, acyloxy, acylamino, silyloxy, amino, nitro, sulfhydryl, alkylthio, imino, amido, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, cyano, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, aralkyl, heteroaralkyl, azido, aziridine, carbamoyl, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, and —(CH 2 ) d —R 80 .
27 . The compound of claim 26 , wherein said compound is complexed with a radionuclide.
28 . The compound of claim 26 , wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.
29 - 51 . (canceled)
52 . A compound represented by E:
wherein
m is an integer in the range 0 to 6 inclusive;
n is an integer in the range 0 to 6 inclusive;
p is an integer in the range of 1 to 10 inclusive;
Z is selected from the group consisting of —CH 2 COOH, alkyl, aryl, aralkyl,
L is selected from the group consisting of
each instance of R 1 is selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, acyl, acyloxy, acylamino, silyloxy, amino, nitro, sulfhydryl, alkylthio, imino, amido, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, cyano, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, aralkyl, heteroaralkyl, azido, aziridine, carbamoyl, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, and —(CH 2 ) d —R 80 ;
R 80 represents independently for each occurrence carboxaldehyde, carboxylate, carboxamido, alkoxycarbonyl, aryloxycarbonyl, ammonium, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, polycyclyl, amino acid, peptide, saccharide, ribonucleic acid, (deoxy)ribonucleic acid, or a ligand for a G-protein-coupled receptor; and
d is an integer in the range 0 to 12 inclusive.
53 . The compound of claim 49 , wherein said compound is complexed with a radionuclide.
54 . The compound of claim 49 , wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.
55 . The compound of claim 49 , wherein L is
R 1 is hydrogen; and Z is alkyl.
56 . A compound represented by F:
wherein
m is independently for each occurrence an integer in the range 0 to 6 inclusive;
n is an integer in the range 0 to 6 inclusive;
L is independently for each occurrence selected from the group consisting of
each instance of R 1 is selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, acyl, acyloxy, acylamino, silyloxy, amino, nitro, sulfhydryl, alkylthio, imino, amido, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, cyano, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, aralkyl, heteroaralkyl, azido, aziridine, carbamoyl, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, and —(CH 2 ) d —R 80 ;
R 80 is independently for each occurrence carboxaldehyde, carboxylate, carboxamido, alkoxycarbonyl, aryloxycarbonyl, ammonium, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, polycyclyl, amino acid, peptide, saccharide, ribonucleic acid, (deoxy)ribonucleic acid, or a ligand for a G-protein-coupled receptor; and
d is an integer in the range 0 to 12 inclusive.
57 . The compound of claim 56 , wherein m is 1.
58 . The compound of claim 56 , wherein n is 1.
59 . The compound of claim 56 , wherein L is
and R 1 is hydrogen.
60 . The compound of claim 56 , wherein L is
R 1 is hydrogen, m is 1; and n is 1.
61 . The compound of claim 56 , wherein said compound is complexed with a radionuclide.
62 . The compound of claim 56 , wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.
63 . A compound represented by G:
wherein
R is H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, aminoacyl, hydroxyacyl, thioacyl, —CO 2 H, —(CH 2 ) d —R 80 , or an amino acid radical;
R 80 is independently for each occurrence carboxaldehyde, carboxylate, carboxamido, alkoxycarbonyl, aryloxycarbonyl, ammonium, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, polycyclyl, amino acid, peptide, saccharide, ribonucleic acid, (deoxy)ribonucleic acid, or a ligand for a G-protein-coupled receptor;
d is an integer in the range 0 to 12 inclusive;
m is independently for each occurrence an integer in the range 0 to 6 inclusive;
n is an integer in the range 0 to 6 inclusive;
L is independently for each occurrence selected from the group consisting of
each instance of R 1 is selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, acyl, acyloxy, acylamino, silyloxy, amino, nitro, sulfhydryl, alkylthio, imino, amido, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, cyano, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, aralkyl, heteroaralkyl, azido, aziridine, carbamoyl, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, and —(CH 2 ) d —R 80 .
64 . The compound of claim 63 , wherein m is 1.
65 . The compound of claim 63 , wherein n is 1.
66 . The compound of claim 63 , wherein R is hydrogen.
67 . The compound of claim 63 , wherein L is
and R 1 is hydrogen.
68 . The compound of claim 63 , wherein L is
R 1 is hydrogen; m is 1; n is 1; and R is hydrogen.
69 . The compound of claim 63 , wherein said compound is complexed with a radionuclide.
70 . The compound of claim 63 , wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.
71 . A compound represented by H:
wherein
R is hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, acyl, acyloxy, acylamino, silyloxy, amino, nitro, sulfhydryl, alkylthio, imino, amido, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, cyano, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, aralkyl, heteroaralkyl, azido, aziridine, carbamoyl, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) d —R 80 ;
R 2 represents a moiety comprising a neutral or anionic Lewis base, H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, aminoacyl, hydroxyacyl, thioacyl, (amino)alkoxycarbonyl, (hydroxy)alkoxycarbonyl, (amino)alkylaminocarbonyl, (hydroxy)alkylaminocarbonyl, —CO 2 H, —(CH 2 ) d —R 80 , or an amino acid radical;
R 80 is independently for each occurrence carboxaldehyde, carboxylate, carboxamido, alkoxycarbonyl, aryloxycarbonyl, ammonium, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, polycyclyl, amino acid, peptide, saccharide, ribonucleic acid, (deoxy)ribonucleic acid, or a ligand for a G-protein-coupled receptor;
d is an integer in the range 0 to 12 inclusive;
m is an integer in the range 0 to 6 inclusive;
n is an integer in the range 0 to 6 inclusive;
L is independently for each occurrence selected from the group consisting of
each instance of R 1 is selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, acyl, acyloxy, acylamino, silyloxy, amino, nitro, sulfhydryl, alkylthio, imino, amido, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, cyano, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, aralkyl, heteroaralkyl, azido, aziridine, carbamoyl, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, and —(CH 2 ) d —R 80 .
72 . The compound of claim 71 , wherein m is 1.
73 . The compound of claim 71 , wherein n is 1.
74 . The compound of claim 71 , wherein R is hydrogen or —(CH 2 ) d —R 80 .
75 . The compound of claim 71 , wherein R 2 is a moiety comprising an anionic Lewis base
76 . The compound of claim 71 , wherein R 2 is a carboxylate, thiolate, or phenolate
77 . The compound of claim 71 , wherein L is
and R 1 is hydrogen.
78 . The compound of claim 71 , wherein L is
R 1 is hydrogen; m is 1; n is 1; R is hydrogen or —(CH 2 ) d —R 80 ; and R 2 is a carboxylate, thiolate, or phenolate.
79 . The compound of claim 71 , wherein said compound is complexed with a radionuclide.
80 . The compound of claim 71 , wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.
81 . A formulation, comprising a compound according to any of claims 26 , 52 , 56 , 63 , 71 , and a pharmaceutically acceptable excipient.
82 . A method of imaging a region in a patient, comprising the steps of: administering to a patient a diagnostically effective amount of a compound of claim 27 , 28 , 53 , 54 , 61 , 62 , 69 , 70 , 79 or 80 ; and obtaining an image of said region of said patient.
83 . The method of claim 82 , wherein said region of said patient is the head or thorax.
84 . A method of preparing a peptide conjugate incorporating a compound of claim 52 , wherein the peptide conjugate is prepared using solid phase synthetic techniques.