Metal radionuclide labeled proteins for diagnosis and therapy

Claim 2

Radionuclide metal chelates, wherein the chelating agent is a N,N'-bis-mercaptoacetyl w,w-1-diamino or diamido aliphatic carboxylic ester or amine having at least four carbon atoms in the carboxylic portion thereof, and wherein the radionuclide metal is a metal or metal oxide radionuclide ion selected from the group consisting of Cu, Tc, Re, Rb, Bi and Pd.

Claim 3

The radionuclide metal chelate according to claim 1, wherein said radionuclide metal is technetium.

Claim 4

The radionuclide metal chelate according to claim 1, wherein said radionuclide metal is rhenium.

Claim 5

The radionuclide metal chelate according to claim 1, wherein said radionuclide metal is chosen from the group consisting of lead, bismuth, palladium, and copper.

Claim 6

A compound of the formula: ##STR30## wherein: M is a metal or metal oxide radionuclide selected from the group consisting of Cu, Tc, Re, Pb, Bi and Pd. one of Z 1 ', Z 2 ', Z 3 ' or Z 4 ' is R'CW'(HNV')n'Y', and the others are H 2 or ═O; R' is an aliphatic, alicyclic, or non-heterocyclic aromatic divalent radical of from 1 to 6 carbon atoms, and 0 to 2 heteroatoms selected from the group consisting of O, S and N; Y' is the leaving group of an active ester, including thioesters, that reacts with a polypeptide in an aqueous medium to form an amide or amidine bond, --NH 2 , --NHNH 2 or a polypeptide of at least about 1000 molecular weight; V' is of the formula R'CW'; W' is ═NH or ═O, with the proviso that the W' bonded to the carbon atom bonded to Y' is H 2 when Y' is --NH 2 or NHNH 2 ; X' is a bond, methylene or CHZ 4 '; each A' is independently selected from H or lower alkyl of from 1 to 6 carbon atoms; and n' is 0 or 1.

Claim 7

A compound of the formula: ##STR30## wherein: M is a metal or metal oxide radionuclide selected from the group consisting of Cu, Tc, Re, Pb, Bi and Pd. one of Z 1 ', Z 2 ', Z 3 ' or Z 4 ' is R'CW'(HNV')n'Y', and the others are H 2 or ═O; R' is an aliphatic, alicyclic, or non-heterocyclic aromatic divalent radical of from 1 to 6 carbon atoms, and 0 to 2 heteroatoms selected from the group consisting of O, S and N; Y' is the leaving group of an active ester, including thioesters, that reacts with a polypeptide in an aqueous medium to form an amide or amidine bond, --NH 2 , --NHNH 2 or a polypeptide of at least about 1000 molecular weight; V' is of the formula R'CW'; W' is ═NH or ═O, with the proviso that the W' bonded to the carbon atom bonded to Y' is H 2 when Y' is --NH 2 or NHNH 2 ; X' is a bond, methylene or CHZ 4 '; each A' is independently selected from H or lower alkyl of from 1 to 6 carbon atoms; and n' is 0 or 1.

Claim 8

The compound according to claim 5, wherein M is technetium.

Claim 9

The compound according to claim 5, wherein M is rhenium.

Claim 10

The compound according to claim 5, wherein M is selected from the group consisting of lead, bismuth, palladium, and copper.

Claim 11

The compound according to claim 5, wherein X' is a bond.

Claim 12

The compound according to claim 5, wherein Y' is a polypeptide.

Claim 13

The compound according to claim 10, wherein said polypeptide is an immunoglobulin or a specific binding fragment thereof.

Claim 14

The compound according to claim 11, wherein said immunoglobulin is a monoclonal antibody.

Claim 15

The compound according to claim 12, wherein said monoclonal antibody is specific for cancer cells.

Claim 16

The compound according to claim 13, wherein said cancer cells are melanoma cells.

Claim 17

The compound according to claim 11, wherein said fragment is selected from the group consisting of a F(ab), F(ab'), F(ab') 2 , and F v fragment of an antibody.

Claim 18

The compound according to claim 15, wherein said fragment is specific for cancer cells.

Claim 19

The compound according to claim 16, wherein said cancer cells are melanoma cells.

Claim 20

The compound according to claim 5, wherein the CW' group adjacent to Y' represents ##STR31## and Y' is the leaving group of an ester capable of reacting with a polypeptide in an aqueous medium to form an amide bond.

Claim 21

The compound according to claim 18, wherein said ester is selected from a 2,3,5,6-tetrafluorophenyl ester and a thiophenyl ester.

Claim 22

The compound according to claim 5, wherein X' is a bond, Z 3 , is ═0, and one of Z 1 or Z 2 is ##STR32## and the other is ═0 or H 2 .

Claim 23

A compound of the formula: ##STR33## wherein M is a metal or metal oxide radionuclide selected from the group consisting of Cu, Tc, Re, Pb, Bi and Pd.

Claim 24

A compound of the formula: ##STR33## wherein M is a metal or metal oxide radionuclide selected from the group consisting of Cu, Tc, Re, Pb, Bi and Pd.

Claim 25

A method of detecting the presence or absence of a target site within a human or mammalian host, comprising the steps of: a) administering an effective amount of the compound of claim 5 to said host, wherein M is a 99m Tc radionuclide and Y' is a polypeptide which binds to said target site; b) waiting for a predetermined length of time to allow accumulation of said compound at said target site; and then, c) detecting the biodistribution of said radionuclide in said host to determine the presence or absence of one or more of said target sites in said host.

Claim 26

The method according to claim 22, wherein, in the determination of the presence or absence of said target site, organs known to naturally accumulate said compound are eliminated from consideration as target sites.

Claim 27

The method according to claim 23, wherein said organs are the kidneys of said host.

Claim 28

The method according to claim 22 wherein said polypeptide is an immunoglobulin or a specific binding fragment thereof.

Claim 29

The method according to claim 25 wherein said fragment is selected from the group consisting of F(ab), F(ab'), F(ab') 2 , and Fv fragments of a monoclonal antibody.

Claim 30

The method according to claim 26 wherein said fragment is specific for cancer cells.

Claim 31

The method according to claim 27 wherein said cancer cells are melanoma cells.

Claim 32

The method according to claim 22 wherein said detection step is accomplished by scanning said human with a gamma camera.

Claim 33

A compound of the formula: ##STR34## wherein: M is a metal or metal oxide radiuclide selected from the group consisting of Cu, Te, Re, Pb, Bi and Pd. one of Z 1 ' Z 2 ', Z 3 ' or Z 4 ' is R'CW'(HNV') n' Y', and the others are H 2 or ═O; R' is an aliphatic, alicyclic, or non-heterocyclic aromatic divalent radical of from 1 to 6 carbon atoms, and 0 to 2 heteroatoms selected from the group consisting of O, S and N; Y' is a polypeptide; V' is of the formula R' CW'; W' is ═NH or ═O; X' is a bond, methylene or CHZ 4 '; each A' is independently selected from H or lower alkyl of from 1 to 6 carbon atoms; and n' is 0 or 1.

Claim 34

A compound of the formula: ##STR34## wherein: M is a metal or metal oxide radiuclide selected from the group consisting of Cu, Te, Re, Pb, Bi and Pd. one of Z 1 ' Z 2 ', Z 3 ' or Z 4 ' is R'CW'(HNV') n' Y', and the others are H 2 or ═O; R' is an aliphatic, alicyclic, or non-heterocyclic aromatic divalent radical of from 1 to 6 carbon atoms, and 0 to 2 heteroatoms selected from the group consisting of O, S and N; Y' is a polypeptide; V' is of the formula R' CW'; W' is ═NH or ═O; X' is a bond, methylene or CHZ 4 '; each A' is independently selected from H or lower alkyl of from 1 to 6 carbon atoms; and n' is 0 or 1.

Claim 35

The compound of claim 30 wherein said polypeptide is an immunoglobulin or a specific binding fragment thereof.

Claim 36

The compound of claim 31 wherein said immunoglobulin or specific binding fragment thereof is a monoclonal antibody or monoclonal antibody fragment.

Claim 37

The compound of claim 30 wherein X' is a bond, Z 3 ' is ═O, and one of Z 1 ' or Z 2 ' is ##STR35## and the other is ═O or H 2 .

Claim 38

The compound of claim 30 wherein M is technetium or rhenium.