Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals

A method of producing a compound of formula (I),

• wherein:
• L is a nitrogen containing macrocyclic metal ligand;
• X is a linking moiety;
• Y is selected from the group consisting of OR, SR1 and N(R2)2;
• R is independently selected from the group consisting of H, an oxygen protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl;
• R1 is independently selected from the group consisting of H, a sulfur protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl;
• and
• each R2 is independently selected from the group consisting of H, a nitrogen protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl;
• or a pharmaceutically acceptable salt or complex thereof, the method comprising:
• reacting an amino substituted metal chelating ligand or a metal complex thereof of the formula:
• L-NH2
• wherein L is a nitrogen containing macrocyclic metal ligand;
• with an activated dicarbonyl compound of the formula (III)
• wherein Z is O, S or NR2;
• and
• (b) isolating the compound of formula (I) or a metal complex thereof;
• wherein L is
• V is selected from the group consisting of N and CR4;
• each Rx and Ry are independently selected from the group consisting of H, CH3, 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,
• R4 is selected from the group consisting of H, OH, halogen, NO2, NH2, optionally substituted C1-C12alkyl, optionally substituted C6-C18aryl, cyano, CO2R5, NHR5, N(R5)2 and a group of the formula:
• wherein
• X1 is a linking moiety;
• Y1 is selected from the group consisting of OR6, SR7, N(R8)2 and a molecular recognition moiety;
• wherein R5 is H or C1-C12alkyl,
• wherein R6 is selected from the group consisting of H, halogen, an oxygen protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12-alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl;
• wherein R7 is selected from the group consisting of H, halogen, a sulfur protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12-alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl;
• wherein R8 is independently selected from the group consisting of H, halogen, a nitrogen protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12-alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl.