	US 12,419,976 B2
	Hybrid tracers for targeted cancer imaging and treatment
Fijs W. B. Van Leeuwen, ZA Leiden (NL); Hans-Jurgen Wester, Munich (DE); Tessa Buckle, ZA Leiden (NL); Danny Van Willigen, ZA Leiden (NL); Margret Schottelius, Munich (DE); and Saskia Kropf, Fürstenfeldbruck (DE)
Assigned to ACADEMISCH ZIEKENHUIS LEIDEN (H.O.D.N. LUMC) GMBH, (NL); SCINTOMICS GMBH, (DE); and TECHNISCHE UNIVERSITÄT MÜNCHEN, (DE)
Appl. No. 17/283,761
Filed by ACADEMISCH ZIEKENHUIS LEIDEN (H.O.D.N. LUMC), ZA Leiden (NL); TECHNISCHE UNIVERSITÄT MÜNCHEN, Munich (DE); and SCINTOMICS GMBH, Fürstenfeldbruck (DE)
PCT Filed Oct. 11, 2019, PCT No. PCT/EP2019/077600 § 371(c)(1), (2) Date Apr. 8, 2021, PCT Pub. No. WO2020/074705, PCT Pub. Date Apr. 16, 2020.
Claims priority of application No. 18199963 (EP), filed on Oct. 11, 2018.
Prior Publication US 2021/0338841 A1, Nov. 4, 2021
Int. Cl. A61K 49/10 (2006.01); A61K 49/00 (2006.01); A61K 51/04 (2006.01); C07D 403/06 (2006.01); C07D 403/14 (2006.01)

CPC A61K 49/106 (2013.01) [A61K 49/0002 (2013.01); A61K 51/0482 (2013.01); C07D 403/06 (2013.01); C07D 403/14 (2013.01)]

17 Claims

1. A hybrid tracer of formula I or Ia:

wherein:

R₁is selected from sulfonate, carboxyl, phosphonate, and H and R₂is H;

R₃is selected from sulfonate, carboxyl, phosphonate, and H and R₄is H;

wherein one of R₁and R₃is selected from sulfonate, carboxyl, phosphonate and the other of R₁and R₃is H;

each of R₅and R₆is H;

each of R₇, R₈, R₉and R₁₀is independently selected from sulfonate, carboxyl, phosphonate, CH₃, CH₂CH₃and H;

each of

V is —CH₂— or —CH₂CH₂O—;

W is —CH₂— or —CH₂CH₂O—;

Y₁is —EuK, —EuFA, —EuPG, or -L₃-EuE;

Y₂is -L₄-EuK, -L₄-EuFA, -L₄-EuPG, or —EuE;

Z is a chelating moiety comprising a residue of bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N′-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]amino] pentyl]-N-hydroxybutandiamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecan (DO2A), N,N′-dipyridoxylethylendiamine-N,N′-diacetate-5,5′-bis(phosphat) (DPDP), ethylenediamine-N,N′-tetraacetic acid (EDTA), ethyleneglykol-O,O-bis(2-aminoethyl)-N,N,N′,N′-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N′-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecan-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononan-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carbooxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8, 11-tetraacetic acid (TETA), terpyridin-bis(methyleneamintetraacetic acid (TMT), 1,4,7,10-tetraazacyclo-tridecan-N,N′,N″,N″-tetraacetic acid (TRITA), triethylenetetraaminehexaacetic acid (TTHA), N,N′-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H₂macropa), or 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl} heptanedioic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide](THP); or Z is -MAS₃, -MAG₃, -DOTA-GA, -DOTA, or -DTPA, or a residue thereof;

L₃is a linker of formula —NH—R₁₄—NH—, where R₁₄is a substituted or unsubstituted alkyl, selected from a residue of lysine, a residue of ornithine or —NH—(C₄-C₇alkyl)-NH—;

L₄is a linker of formula —C(O)—R₁₅—C(O)—, where R₁₅is a substituted or unsubstituted alkyl, selected from a residue of aspartic acid, a residue of glutamic acid or —C(O)—(C₄-C₇alkyl)-C(O)—;

n is 2 or 3;

m is 4, 5, 6, 7 or 8; and

p is 3, 4, 5, 6, 7 or 8,

or a pharmaceutically acceptable salt thereof;

wherein —EuK is