| 主权项 |
1. A Ga68 complex of formula FOLATE-(LINKER)i-NOTA-Ga68, wherein:
FOLATE is a folate compound or a derivative thereof capable of targeting a folate receptor; NOTA is a chelate capable of complexing Ga68 having a NOTA scaffold or derivatives thereof; LINKER is a chemical group linking FOLATE and NOTA; i is an integer chosen between 0 and 1; wherein
NOTA is formula (I): whereinY2 is: —(C═O)—Y4, —Y4 or NR4-CH2—(C═O)—Y4,each of Y3 is independently —(C═O)—Y4 or wherein
* is the binding site to NOTA;Y4 is —OH, or —NHR;R is a C1-C6 alkyl group;R4 is a hydrogen atom, a group —CH2COOH and a benzyl group;R1 is a hydrogen atom or a phenyl group substituted by the group NCS;R2 is hydrogen, —(CH2)j-COOH, —(CH2)j-NH2, —(CH2)j-CO-Y, or —(CH2)j-NHY, in which j is an integer from 1 to 10, and Y is the binding site to LINKER when i=1, or to FOLATE when i=0;n is an integer from 0 to 2;k=0 or 1;when i=1, X1 is a group of formula —(CH2)p—X3, wherein p is an integer of between 0 and 10, and X3 is the binding site between NOTA and LINKER when i=1 and X3 is selected from the group consisting of: —CONH—, —COO—, —NHCO—, —NH—, —CO— and —OCO—,
orX1 is a benzyl group substituted by an NO2 group, a phenyl group substituted by a NCS or an OH group, or a group of formula: wherein * is the binding site to the NOTA,orwhen i=0, X1 is FOLATE;R3 is a hydrogen atom, a benzyl group substituted by an NO2 group, a phenyl group substituted by an NCS or an OH group, a —(CH2)2—COOH group, or a group of formula: wherein * is the binding site to NOTA FOLATE is formula (A): or (B): or tautomers thereof, wherein
* is the site where FOLATE is bound to LINKER when i=1, or to NOTA when i=0;a) G1 is selected from the group consisting of: a halogen atom, Rf2, ORf2, SRf3 and NRf4Rf5;b) G2 is selected from the group consisting of: a halogen atom, Rf2, ORf2, SRf3 and NRf4Rf5;c) G3 is —(Rf6′)C═ or —N═, and G4 is —(Rf6′)C— or —N—, or
G3 is —(Rf6′)C— or —N—, and G4 is —(Rf6′)C═ or —N═, orG3 and G4 are each independently, —(Rf6′)C(Rf7′)— or —N(Rf4′)—;d) G5 is absent or selected from the group consisting of: —(Rf6′)C═, —N═, —(Rf6′)C(Rf7′)— and —N(Rf4′)—;e) J is a 5- or 6- membered aryl or heteroaryl group;f) G6 is N or C;g) K1 and K2 are each selected independently from the group consisting of; —C(Zf)—, —C(Zf)O—, —OC(Zf)—, —N(Rf4″)—, —C(Zf)—N(Rf4), —N(Rf4″)—C(Zf), —O—C(Zf)—N(Rf4″)—, —N(Rf4″)—C(Zf)—O—, N(Rf4″)—C(Zf)—N(Rf5″)—, —O—, —S—, —S(O)—, —S(O)2—, —N(Rf4″)S(O)2—, —C(Rf6″)(Rf7″)—, —N(C≡CH)—, —N(CH2—C≡CH)—, C1-C12 alkyl and C1-C12 alkoxy, wherein Zf is O or S;h) Rf2, Rf3, Rf4, Rf4′, Rf4″, Rf5, Rf5″, Rf6″ and Rf7″ are each selected independently from the group consisting of: H, a halogen atom, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino) carbonyl;i) Rf6′ and Rf7′ are each selected independently from the group consisting of: H, a halogen atom, C1-C12 alkyl and C1-C12 alkoxy, or Rf6′ and Rf7′ together form O═;j) R6 and R7 are each independently H or C1-C12 alkyl;k) Lf is glutamine;l) p, r and s are independently 0 or 1; andm) x is an integer of 1 to 5; and LINKER is:
a single bond; orselected from the group consisting of:
—(CH2)m—, —(CH2)mCO—, —(CH2)mNHCO—, —(CH2)mCONH—, —(CH2)mCONH(CH2)m, —(CH2)mphenylNH—, —(CH2)mNH—, —NH(CH2)mNH—, —(CH2)mphenyl-, and —NH(CH2)m—, wherein m is an integer from 1 to 20;(CH2CH2O)q(CH2)rCO—, (CH2CH2O)q(CH2)rNH—CO—, —(CH2CH2O)q(CH2)r—, and (CH2CH2O)q(CH2)rNH—, wherein q is an integer from 1 to 10, and r is an integer from 2 to 10;—(CH2)n—CONH-PEG-, wherein * is the binding site to NOTA, and n is an integer from 1 to 5;—CO—CH2—O—(CH2)r—O—(CH2)p—O—CH2—CO—, —CO—(CH2)r—CO2—(CH2)p—OCO—(CH2)s—CO—, —CO—CH(OH)—CH(OH)—CO—, CO—(CH2)r—CO—, —CO—CH2—O—(CH2)r—O—(CH2)p—O—CH2—, —CO—(CH2)r—CO2—(CH2)p—OCO—(CH2)s—, —CO—CH(OH)—CH(OH)— and —CO—(CH2)r—, wherein r is an integer from 1 to 20, p is an integer from 1 to 20, and s is an integer from 1 to 20;—NH—(CH2)t—CO—, —NH—CH2—(CH2—O—CH2)t—CO— and —NH—CH2—(CH2—O—CH2)t, wherein t is an integer from 1 to 10;
andP1-l-P2, wherein P1 and P2 are independently selected from the group consisting of: O, S, NH, absent, CO2, NHCO, CONH, NHCONH, NHCSNH, SO2NH—, NHSO2— and squarate, and wherein l is selected from the group consisting of: alkyl, alkoxyalkyl, polyalkoxyalkyl, polyethylene glycol, alkyl interrupted with one or more squarates or with one or more aryls, alkenyl, alkynyl, and alkyl interrupted with one or more groups selected from: —NH—, —O—, —CO—, —NH(CO)—, —(CO)NH—, —O(CO)—, and —(OC)O—, andwherein NOTA is complexed to Ga68. |
