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US 10,894,807 B2Granted
PSMA imaging agents
AssigneeSiemens Medical Solutions USA, Inc.
InventorsEric Wang, Hartmuth C. Kolb, Anna Katrin Szardenings, Changhui Liu, Joseph C. Walsh, Gang Chen, Anjana Sinha, Dhanalakshmi Kasi, Chul Yu, Umesh B. Gangadharmath, Wei Zhang, Tieming Zhao, Vani P. Mocharla
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Abstract
Compounds for targeting and agents for imaging, prostate-specific membrane antigen (PSMA) are disclosed. Methods of synthesizing compounds and imaging agents, as well as methods for imaging PSMA are also disclosed. The imaging agents disclosed are suitable for PET and SPECT imaging.
Claims36
A method comprising:
- administering to a patient, a radio-labelled compound of Formula I:
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein:
- X1 is CH or N;
- X2 is CH or N;
- X3 is (CH2)1-6 wherein at least one CH2 is optionally replaced by at least one of CONH or aryl;
- X4 is selected from the group consisting of aryl, NH, CH2, and
- X5 is selected from the group consisting of CONH, C(O), (CH2)1-2—C(O) and (CH2)1-2—CONH;
- X6 is aryl or CH;
- X7 is CH or N;
- X8 is CH or N;
- X13 is (CH2)1-5, where at least one CH2 of (CH2)1-5 is replaced by a group selected from aryl, NH, CH2, and
- R1 is selected from the group consisting of alkyne, N3, NO2, —(CH2)1-20—R3 where at least one CH2 of —(CH2)1-20—R3 is optionally replaced by at least one of —O—, aryl, heteroaryl, NH or CONH and wherein at least one H of —(CH2)1-20—R3 is optionally substituted with COOH or NO2;
- and (—CH2—CH2—)1-5—NH2 where at least one CH2 of (—CH2—CH2—O—)1-5—NH2 is optionally replaced by aryl or heteroaryl;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- and
- R3 is selected from the group consisting of COOH, N3, alkyne, protecting group, halo and positron emitting isotope;
- or
- administering to a patient, a radio-labelled compound of Formula II:
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein:
- X1 is CH or N;
- X2 is CH or N;
- X9 is (CH2)1-5 where at least one CH2 is optionally replaced by NH,
- X10 is CH or N;
- X11 is selected from the group consisting of (CH2), aryl, or heteroaryl, wherein at least one H of the aryl or heteroaryl is optionally replaced by NO2,
- X12 is selected from the group consisting of O, CONH and (CH2)1-2 wherein at least one CH2 is optionally replaced by NH;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- R4 is selected from the group consisting of H, alkyne, N3, NO2, —(CH2)1-20—R8 where at least one CH2 of —(CH2)1-20—R8 is optionally replaced by at least one of —O—, aryl, heteroaryl, NH or CONH and wherein at least one H of —(CH2)1-20—R8 is optionally substituted with COOH or NO2;
- R8 is selected from the group consisting of H and —(CH2)1-10—R8 where at least one CH2 of —(CH2)1-10—R8 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
- R5 is selected from the group consisting of H and —(CH2)1-10—R8 where at least one CH2 of —(CH2)1-10R8 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
- and
- R6 is selected from the group consisting of H and —(CH2)1-10—R8 where at least one CH2 of —(CH2)1-10—R9 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
- and
- R8 is selected from the group consisting of COOH, N3, alkyne, protecting group, halo and positron emitting isotope;
- or
- administering to a patient a radio-labelled compound of Formula III:
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein:
- X1 is CH or N;
- X13 is (CH2)1-5 wherein at least one CH2 is optionally replaced by aryl;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- R11 is selected from the group consisting of alkyne, N3, NO2, (CH2)1-10—R12 wherein at least one CH2 is optionally replaced by at least one of CONH, aryl or heteroaryl;
- and
- R12 is selected from the group consisting of N3, alkyne, protecting group, halo and radioisotope;
- scanning the patient using positron emission tomography or single photon emission computed tomography;
- and
- imaging a tissue in the patient.
45 more elements
A compound of Formula III:
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein in Formula III:
- X1 is CH or N;
- X13 is (CH2)1-5 wherein at least one CH2 is optionally replaced by aryl;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- Ru is selected from the group consisting of alkyne, N3, NO2, (CH2)1-10—R12 wherein at least one CH2 is optionally replaced by at least one of CONH, aryl or heteroaryl;
- and
- R12 is selected from the group consisting of N3, alkyne, protecting group, halo and radioisotope.
5 more elements
A method comprising:
- synthesizing a tracer compound of Formulas I;
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein:
- X1 is CH or N;
- X2 is CH or N;
- X3 is (CH2)1-6 wherein at least one CH2 is optionally replaced by at least one of CONH or aryl;
- X4 is selected from the group consisting of aryl, NH, CH2, and
- X5 is selected from the group consisting of CONH, C(O), (CH2)1-2—C(O) and (CH2)1-2—CONH;
- X6 is aryl or CH;
- X7 is CH or N;
- X8 is CH or N;
- X13 is (CH2)1-5, where at least one CH2 of (CH2)1-5 is replaced by aryl, NH, CH2, and
- R1 is selected from the group consisting of alkyne, N3, NO2, —(CH2)1-20—R3 where at least one CH2 of —(CH2)1-20—R3 is optionally replaced by at least one of —O—, aryl, heteroaryl, NH or CONH and wherein at least one H of —(CH2)1-20—R3 is optionally substituted with COOH or NO2;
- and (—CH2—CH2—O—)1-5 NH2 where at least one CH2 of (—CH2—CH2—O—)1-5 NH2 is optionally replaced by aryl or heteroaryl;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- and
- R3 is selected from the group consisting of COOH, N3, alkyne, protecting group, halo and positron emitting isotope;
- or
- synthesizing a radio-labelled compound of Formulas II;
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein:
- X1 is CH or N;
- X2 is CH or N;
- X9 is (CH2)1-5 where at least one CH2 is optionally replaced by NH,
- X10 is CH or N;
- X11 is selected from the group consisting of (CH2), aryl, or heteroaryl, wherein at least one H of the aryl or heteroaryl is optionally replaced by NO2,
- X12 is selected from the group consisting of O, CONH and (CH2)1-2 wherein at least one CH2 is optionally replaced by NH;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- R4 is selected from the group consisting of H, alkyne, N3, NO2, —(CH2)1-20—R8 where at least one CH2 of —(CH2)1-20—R8 is optionally replaced by at least one of —O—, aryl, heteroaryl, NH or CONH and wherein at least one H of —(CH2)1-20—R8 is optionally substituted with COOH or NO2;
- R8 is selected from the group consisting of H and —(CH2)1-10—R8 where at least one CH2 of —(CH2)1-10—R8 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
- R5 is selected from the group consisting of H and —(CH2)1-10—R8 where at least one CH2 of —(CH2)1-10—R8 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
- and
- R6 is selected from the group consisting of H and —(CH2)1-10—R8 where at least one CH2 of —(CH2)1-10—R9 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
- and
- R8 is selected from the group consisting of COOH, N3, alkyne, protecting group, halo and positron emitting isotope;
- or
- synthesizing a radio-labelled compound of Formula III:
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein:
- X1 is CH or N;
- X13 is (CH2)1-5 wherein at least one CH2 is optionally replaced by aryl;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- R11 is selected from the group consisting of alkyne, N3, NO2, (CH2)1-10—R12 wherein at least one CH2 is optionally replaced by at least one of CONH, aryl or heteroaryl;
- and
- R12 is selected from the group consisting of N3, alkyne, protecting group, halo and radioisotope;
- and
- reacting a compound of any of Formulas I-III, wherein in any of Formulas I-III, at least one H of R1, R3, R4, R8, R11, R12, R13, R15 and R16 is replaced by either a first alkyne or a first azide with a second azide or second alkyne having a radioisotope or halo.
44 more elements
A method comprising:
- administering to a patient, a radio-labelled compound of Formula I:
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein:
- X1 is CH or N;
- X2 is CH or N;
- X3 is (CH2)1-6 wherein at least one CH2 is optionally replaced by at least one of CONH or aryl;
- X4 is selected from the group consisting of aryl, NH, CH2, and
- X5 is selected from the group consisting of CONH, C(O), (CH2)1-2—C(O) and (CH2)1-2—CONH;
- X6 is aryl or CH;
- X7 is CH or N;
- X8 is CH or N;
- X13 is (CH2)1-5, where at least one CH2 of (CH2)1-5 is replaced by a group selected from aryl, NH, CH2, and
- R1 is selected from the group consisting of alkyne, N3, NO2, —(CH2)1-20—R3 where at least one CH2 of —(CH2)1-20—R3 is optionally replaced by at least one of —O—, aryl, heteroaryl, NH or CONH and wherein at least one H of —(CH2)1-20—R3 is optionally substituted with COOH or NO2;
- and (—CH2—CH2—O—)1-5—NH2 where at least one CH2 of (—CH2—CH2—O—)1-5—NH2 is optionally replaced by aryl or heteroaryl;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- and
- R3 is selected from the group consisting of COOH, N3, alkyne, protecting group, halo and positron emitting isotope;
- or
- administering to a patient, a radio-labelled compound of Formula II:
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein:
- X1 is CH or N;
- X2 is CH or N;
- X9 is (CH2)1-5 where at least one CH2 is optionally replaced by NH,
- X10 is CH or N;
- X11 is selected from the group consisting of (CH2), aryl, or heteroaryl, wherein at least one H of the aryl or heteroaryl is optionally replaced by NO2,
- X12 is selected from the group consisting of O, CONH and (CH2)1-2 wherein at least one CH2 is optionally replaced by NH;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- R4 is selected from the group consisting of H, alkyne, N3, NO2, —(CH2)1-20—R8 where at least one CH2 of —(CH2)1-20—R8 is optionally replaced by at least one of —O—, aryl, heteroaryl, NH or CONH and wherein at least one H of —(CH2)1-2—R8 is optionally substituted with COOH or NO2;
- R8 is selected from the group consisting of H and —(CH2)1-10—R8 where at least one CH2 of —(CH2)1-10—R8 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
- R5 is selected from the group consisting of H and —(CH2)1-10—R8 where at least one CH2 of —(CH2)1-10—R8 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
- and
- R6 is selected from the group consisting of H and —(CH2)1-10—R8 where at least one CH2 of —(CH2)1-10—R9 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
- and
- R8 is selected from the group consisting of COOH, N3, alkyne, protecting group, halo and positron emitting isotope;
- or
- administering to a patient, a radio-labelled compound of Formula III:
- and pharmaceutically acceptable salts and stereoisomers thereof,
- wherein:
- X1 is CH or N;
- X13 is (CH2)1-5 wherein at least one CH2 is optionally replaced by aryl;
- R2 is selected from the group consisting of H, COOH or CH2—COOH;
- R11 is selected from the group consisting of alkyne, N3, NO2, (CH2)1-10—R12 wherein at least one CH2 is optionally replaced by at least one of CONH, aryl or heteroaryl;
- and
- R12 is selected from the group consisting of N3, alkyne, protecting group, halo and radioisotope;
- wherein in any of Formulas I-III, at least one H of R1, R3, R4, R8, R11, R12, R13, R15 and R16 is replaced by either a first alkyne or a first azide with a second azide or second alkyne having a radioisotope or halo.
43 more elements
Dependencies are inferred from the claim text.