LIGANDS FOR IMAGING CARDIAC INNERVATION
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Abstract
Novel compounds that find use as imaging agents within nuclear medicine applications (PET imaging) for imaging of cardiac innervation are disclosed. These PET based radiotracers may exhibit increased stability, decreased NE release (thereby reducing side effects), improved quantitative data, and/or high affinity for VMAT over prior radiotracers. Methods of using the compounds to image cardiac innervation are also provided. In some instances the compounds are developed by derivatizing certain compounds with 18F in a variety of positions: aryl, alkyl, a keto, benzylic, beta-alkylethers, gamma-propylalkylethers and beta-proplylalkylethers. Alternatively or additionally, a methyl group a is added to the amine, and/or the catechol functionality is either eliminated or masked as a way of making these compounds more stable.
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Citations
45 Claims
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1-25. -25. (canceled)
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26. A compound having Structure Delta or Structure II, as follows:
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wherein for Structure Delta, linking groups B, D, E, F, and G are independently selected from the group consisting of a bond, alkyl, aryl, aralkyl, alkylaryl, heteroaryl, alkoxy, alkylamino, aminoalkyl, aryloxy, alkoxyalkyl, thioalkyl, and heterocyclyl; R8 through R14 are independently selected from the group consisting of H, OR3, F, Cl, Br, I, CH2F, OCH2CH2F, alkyl (C1-C4), aryl, heteroaryl, C(═
O)R3, CO2R3, and image moiety (Im);R3, R4, R5, and R6 are independently selected from the group consisting of H, alkyl, aryl, aralkyl, heteroaryl, alkylamino, alkyloxy, and aryloxy, and optionally any two of R4, R5, R6, R13, or R14 may form a cyclic structure selected from the group consisting of a bond, —
CH2—
, —
CH2—
CH2—
, —
CH2—
CH2—
CH2—
, —
CH═
CH—
, —
X═
CH—
, and —
X—
CH═
CH—
, wherein X is selected from the group consisting of O, NH, N═
, and NR7, and R7 is selected from the group consisting of alkyl, aryl and heteroaryl substituents;wherein for Structure II, linking groups B, D, E, F and G are independently selected from the group consisting of a bond, alkyl, aryl, aralkyl, alkylaryl, heteroaryl, alkoxy, alkylamino, aryloxy, alkoxyalkyl, and heterocyclic; and R6 through R12 are independently selected from the group consisting of H, OR4, F, Cl, CF3, Br, I, alkyl (C1-C4), aryl, heteroaryl, C(O)R4, CO2R4, N(R4)2, CN, C(═
NH)NHR5, C(═
O)NHR5, NHC(═
O)NR5, NHNR5, SO2OR5, and Im, andR4 and R5 are selected from the group consisting of H, alkyl, aryl, and heteroaryl substituents. - View Dependent Claims (27, 28, 29, 30, 31, 32, 42, 43, 44, 45)
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44. An injection dose for imaging cardiac innervation comprising a compound of claim 26, and optionally one or more excipients, suitable for administration by injection to a patient.
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45. The injection dose of claim 44, wherein the compound has the structure:
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33. A compound having Structure Chi as follows:
wherein R, R1 and R2 are independently selected from the group consisting of H, OR3, F, Cl, Br, I, CH2F, OCH2CH2F, alkyl (C1-C4), aryl, heteroaryl, aralkyl, alkylaryl, C(O)R3, CO2R3, imaging moiety (Im), and OCH2CH2Im; and wherein R3 is selected from the group consisting of H, alkyl, aryl, and heteroaryl substituents. - View Dependent Claims (34, 35)
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36. A compound having Structure Alpha as follows:
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wherein n=0, 1, 2 or 3; and
R, R1, R2 and R3 are independently selected from the group consisting of H, OR4, F, Cl, Br, I, CF3, alkyl (C1-C4), aryl, heteroaryl, C(═
O)R4, CO2R4, N(R4)2, CN, C(═
NR4)OR5, NR4(C(═
NR5)NHR6, C(═
NR4)NHR3, C(═
O)NHR4, NR4C(═
O)NR5, NR4NR5, SO2OR4, and imaging moiety (Im),wherein R4, R5, and R6 are selected from the group consisting of H, alkyl, aryl and heteroaryl substituents; W, X, Y and Z can independently be selected from the group consisting of H, OR4, N(R4)2, F, Cl, Br, I, CF3, Im, aryl, and heteroaryl, or optionally the compound comprises a linking group Q between Y and Z, wherein Q is selected from the group consisting CH, CH2, N, NH, and O; and A is O or absent. - View Dependent Claims (37, 38, 39, 40, 41)
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41. The compound of claim 36, having the structure:
Specification