PSMA-targeting ligands with optimal properties for imaging and therapy
Theranostic agents incorporating a chelating moiety that can chelate a radioactive metal isotope and a PSMA-targeting moiety are disclosed herein. The theranostic agents, which can be used to treat and/or detect cancers associated with increased PSMA expression, have the formula: and include complexes, anions or salts thereof. R 1 includes a chelating moiety; a is 0 or 1; n is an integer from 12 to 21; and R 2 includes a prostate specific membrane antigen (PSMA)-targeting moiety. Optionally, the chelating moiety is chelated to a metal atom, where the metal atom is a positron or single photon emitting metal isotope, or an alpha, beta, or Auger emitting metal isotope.
1. A method for treating cancer associated with increased PSMA expression in a subject, comprising:
administering to the subject a therapeutically effective amount of a composition comprising a theranostic agent, wherein the theranostic agent has the formula:
or a complex, anion or salt thereof, wherein:
R 1 comprises a chelating moiety;
a is 1;
n is 17; and
R 2 comprises a prostate specific membrane antigen (PSMA)-targeting moiety, wherein the theranostic agent comprises a metal atom chelated to the chelating moiety, and wherein the metal atom is an alpha, beta, or Auger emitting metal isotope.
2. The method of claim 1 , wherein the chelating moiety is anionic and selected such that the theranostic agent as a whole is electrically neutral.
3. The method of claim 1 , wherein the metal isotope is selected from the group consisting of Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.
4. The method of claim 1 , wherein the chelating moiety is selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) and its derivatives; 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) and its derivatives; 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives; 1,4,7-triazacyclononane,1-glutaric acid-4,7-diacetic acid (NODAGA) and its derivatives; 1,4,7,10-tetraazacyclodecane,1-glutaric acid-4,7,10-triacetic acid (DOTAGA) and its derivatives; 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) and its derivatives; 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) and its derivatives; diethylene triamine pentaacetic acid (DTPA), its diester, and its derivatives; 2-cyclohexyl diethylene triamine pentaacetic acid (CHX-A″-DTPA) and its derivatives; deforoxamine (DFO) and its derivatives; 1,2-[[6-carboxypyridin-2-yl]methylamino]ethane (H 2 dedpa) and its derivatives; HOPO and its derivative; MACROPA and its derivatives; and DADA and its derivatives, wherein DADA has the structure:
5. The method of claim 1 , wherein R 1 is selected from the group consisting of:
and anions thereof.
6. The method of claim 1 wherein the PSMA-targeting moiety comprises a thiol-based PSMA binding motif, a phosphorus-based PSMA binding motif, or a urea-based PSMA binding motif.
7. The method of claim 6 , wherein the PSMA-targeting moiety comprises a urea-based PSMA binding motif.
8. The method of claim 7 , wherein R 2 is:
9. The method of claim 8 , wherein the theranostic agent has the formula: