Cage amine ligands for metallo-radiopharmaceuticals

摘要

The present invention relates to compounds that are useful as metal ligands and which can be bound to a biological entity such as a molecular recognition moiety and methods of making these compounds. Once the compounds that are bound to a biological entity are coordinated with a suitable metallic radionuclide, the coordinated compounds are useful as radiopharmaceuticals in the areas of radiotherapy and diagnostic imaging. The invention therefore also relates to methods of diagnosis and therapy utilizing the radiolabelled compounds of the invention.

主权项

1. A method of functionalizing a compound of the formula (1) or a metal complex thereof: wherein Lig is a nitrogen containing macrocyclic metal ligand of the formula V is selected from the group consisting of N and CR1; each Rx and Ry are independently selected from group consisting of H, CH3, and CO2H, NO2, CH2OH, H2PO4, HSO3, CN, CONH2 and CHO; each p is independently an integer selected from the group consisting of 2, 3, and 4; R1 is selected from the group consisting of H, OH, halogen, NO2, NH2, optionally substituted C1-C12alkyl, optionally substituted C6-C18aryl, cyano, CO2R2, NHR3 and N(R3)2; R2 is selected from the group consisting of H, halogen, an oxygen protecting group, substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl; and each R3 is independently selected from the group consisting of H, a nitrogen protecting group, optionally substituted C1-C12alkyl, —(C═O)-substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl; L is a group of the formula
—(CH2)a—, wherein optionally one or more of the CH2 groups may be independently replaced by a heteroatomic group selected from S, O and NR4 where R4 is selected from the group consisting of H, optionally substituted C1-C12alkyl optionally substituted C3-C12cycloalkyl optionally substituted C6-C18aryl, and optionally substituted C1-C18heteroaryl; a is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; the method comprising;(a) converting the compound of formula (1) or a metal complex thereof to a compound of formula (II) or a metal complex thereof wherein L1 is a spacer group of the formula
—(CH2)a—, wherein optionally one or more of the CH2 groups may be independently replaced by a heteroatomic group selected from S, O and NR4 where R4 is selected from the group consisting of H, optionally substituted C1-C12alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl, and optionally substituted C1-C18heteroaryl; a is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;(b) converting the compound of formula (2) or a metal complex thereof to a compound of formula (3) or a metal complex thereof wherein R or a protected form thereof is a moiety capable of binding to a molecular recognition moiety.