US 4,988,496 AGranted

Metal radionuclide chelating compounds for improved chelation kinetics

AssigneeNeoRx Corporation

InventorsAnanthachari Srinivasan, Alan R. Fritzberg, David S. Jones

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Abstract

The present invention provides metal chelating compounds, to chelates and chelate-targeting agent conjugates formed from the chelating compounds, and to methods for making and using these compositions. The chelating compounds incorporate two nitrogen atoms and three sulfur atoms ("N.sub.2 S.sub.3 "), two nitrogen atoms and four sulfur atoms ("N.sub.2 S.sub.4 "), or three nitrogen atoms and three sulfur atoms ("N.sub.3 S.sub.3 "). Metals, and metal oxides, capable of being chelated by the compounds include those that are radionuclides, such as .sup.99m Tc and .sup.186/188 Re. The targeting agent portion of the chelate-targeting agent conjugates provided includes antibodies, peptides, hormones, enzymes and biological response modifiers. Methods for making the conjugates are provided and encompass the addition of a metal, or metal oxide, to a chelating compound prior to attachment to a targeting agent as well as subsequent to the attachment. Another aspect of the invention provides kits for producing chelate-targeting agent comjugates for radiopharmaceutical use. An additional aspect of the invention provides methods for using the chelate-targeting agent conjugates for diagnostic and therapeutic purposes, such as detection of a target site and delivery of a radionuclide to the site, respectively.

Claims13

Dependent claims

A metal chelate having the formula:

##STR25## wherein:
M is a metal, or metal oxide, radionuclide which is chelated;
X.sub.1 and X.sub.2 are H or .dbd.0, but both are not .dbd.0;
X.sub.3 and X.sub.4 are H or .dbd.0, but both are not .dbd.0;
A is H, alkyl group of C.sub.6 or less, --CH.sub.2 --CH.sub.2 --S--R.sub.1, or --CO--CH.sub.2 --S--R.sub.1, with the proviso that when X.sub.1 or X.sub.2 is .dbd.0, A is H;
A' is H, alkyl group of C.sub.6 or less, --CH.sub.2 --CH.sub.2 --S--R.sub.2, or --CO--CH.sub.2 --S--R.sub.2, with the proviso that when X.sub.3 or X.sub.4 is .dbd.0, A' is H;
Y is
(a) --CH.sub.2 --S--R.sub.3, or H, when A is H or an alkyl group of C.sub.6 or less and A'is H or an alkyl group of C.sub.6 or less, or
(b) H, with the proviso that Y must be selected from (a) when A is H or an alkyl group of C.sub.6 or less and A' is H or an alkyl group of C.sub.6 or less;
Y' is
(a) --CH.sub.2 --S--R.sub.4, or H, when A is H or an alkyl group of C.sub.6 or less and A' is H or an alkyl group of C.sub.6 or less, with the proviso that Y and Y' are not both H, or
(b) H, with the proviso that Y' must be selected from (a) when A is H or an alkyl group of C.sub.6 or less and A' is H or an alkyl group of C.sub.6 or less;
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from sulfur protecting groups;
Q is H or a polar group to increase the hydrophilicity of the compound;
n is 0 to 2;
and
z is --(W).sub.m --R', where W is --CH.sub.2 --, --CH.sub.2 --O--, --CH.sub.2 --CO--, or combinations thereof, m is 0 to 5, and R'is a chemically reactive group, with the provisos that when Z is attached to the carbon designated .alpha. there is either no X.sub.1 or no Q at .alpha., that when Z is attached to the carbon designated .beta. there is either no X.sub.3 or no Q at .beta., that when X.sub.1 is .dbd.0 there is no Z at .beta., and that when X.sub.3 is .dbd.0 there is no Z at .beta..

14 more elements

A chelate-targeting agent conjugate having the formula:

##STR26## wherein:
M is a metal, or metal oxide, radionuclide which is chelated;
X.sub.1 and X.sub.2 are H or .dbd.0, but both are not .dbd.0;
X.sub.3 and X.sub.4 are H or .dbd.0, but both are not .dbd.0;
A is H, alkyl group of C.sub.6 or less, --CH.sub.2 --CH.sub.2 --S--R.sub.1, or --CO--CH.sub.2 --S--R.sub.1, with the proviso that when X.sub.1 or X.sub.2 is .dbd.0, A is H;
A' is H, alkyl group of C.sub.6 or less, --CH.sub.2 --CH.sub.2 --S--R.sub.2, or --CO--CH.sub.2 --S--R.sub.2, with the proviso that when X.sub.3 or X.sub.4 is .dbd.0, A' is H;
Y is
(a) --CH.sub.2 --S--R.sub.3, or H, when A is H or an alkyl group of C.sub.6 or less and A'is H or an alkyl group of C.sub.6 or less, or
(b) H, with the proviso that Y must be selected from (a) when A is H or an alkyl group of C.sub.6 or less and A' is H or an alkyl group of C.sub.6 or less;
Y' is
(a) --CH.sub.2 --S--R.sub.4, or H, when A is H or an alkyl group of C.sub.6 or less and A' is H or an alkyl group of C.sub.6 or less, with the proviso that Y and Y' are not both H, or
(b) H, with the proviso that Y' must be selected from (a) when A is H or an alkyl group of C.sub.6 or less and A' is H or an alkyl group of C.sub.6 or less;
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from sulfur protecting groups;
Q is H or a polar group to increase the hydrophilicity of the compound;
n is 0 to 2;
and
Z' is --(W).sub.m --Targeting agent, where W is --CH.sub.2 --, --CH.sub.2 --O--, --CH.sub.2 --CO--, or combinations thereof, m is 0 to 5, and Targeting agent includes a linking group, with the provisos that when Z' is attached to the carbon designated a there is either no X.sub.1 or no Q at .alpha., that when Z' is attached to the carbon designated .beta. there is either no X.sub.3 or no Q at .beta., that when X.sub.1 is .dbd.0 there is no Z' at .alpha., and that when X.sub.3 is .dbd.0 there is no Z' at .beta..

14 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/201,134Filed 31 May 1988
Granted: 29 Jan 1991
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 209/48
Iso-indoles; Hydrogenated iso-indoles: with oxygen atoms in positions 1 and 3, e.g. phthalimide
A61K 47/6887
The modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site: antibody-chelate conjugates using chelates…
A61K 51/1093
Antibodies or immunoglobulins; Fragments thereof , the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised…
C07C 327/30
Esters of monothiocarboxylic acids: having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals…