| 主权项 |
1. A method for diagnosis and visualization of tumor necrotic domains by minimally invasive imaging of tumors, said method comprising:
(i) administering to a subject suspected of having a tumor with necrotic domains a conjugate of an RGD-containing peptide or a non-peptidic compound that mimics a peptide and has the RGD motif and a photosensitizer; (ii) imaging the subject at least 24-48 hours after said administration; and (iii) diagnosing the presence or absence of said tumor necrotic domains, wherein said photosensitizer is a chlorophyll or bacteriochlorophyll of the formula II:wherein
M represents 2H or an atom selected from the group consisting of Mg, Pd, Pt, Co, Ni, Sn, Cu, Zn, Mn, In, Eu, Fe, Au, Al, Gd, Dy, Er, Yb, Lu, Ga, Y, Rh, Ru, Si, Ge, Cr, Mo, P, Re, Tc and Ti and isotopes and radio-isotopes thereof; R1, R′2 and R6 each independently is Y—R8, —NR9R′9 or —N+R9R′9R″9A−; or R1 and R6 together form a ring comprising an RGD-containing peptide or a residue of a non-peptidic compound that mimics a peptide and has the RGD motif; Y is O or S; R4 is —CH═CR9R′9, —CH═CR9Hal, —CH═CH—CH2—NR9R′9, —CH═CH—CH2—N+R9R′9R″9A−, —CHO, —CH═NR9, —CH═N+R9R′9A−, —CH2—OR9, —CH2—SR9, —CH2-Hal, —CH2—R9, —CH2—NR9R′9, —CH2—N+R9R′9R″9A−, —CH2—CH2R9, —CH2—CH2Hal, —CH2—CH2OR9, —CH2—CH2SR9, —CH2—CH2—NR9R′9, —CH2—CH2—N+R9R′9R″9A−, —COCH3, —C(CH3)═CR9R′9, —C(CH3)═CR9Hal, —C(CH3)═NR9, —CH(CH3)═N+R9R′9A−, —CH(CH3)-Hal, —CH(CH3)—OR9, —CH(CH3)—SR9, —CH(CH3)—NR9R′9, —CH(CH3) —N+R9R′9R′9A−, or —C≡CR9; R′4 is methyl or formyl; R8, R9, R′9 and R″9 each independently is: (a) H; (b) C1-C25 hydrocarbyl; (c) C1-C25 hydrocarbyl substituted by one or more functional groups selected from the group consisting of halogen, nitro, oxo, OR, SR, epoxy, epithio, —CONRR′, —COR, COOR, —OSO3R, —SO3R, —SO2R, —NHSO2R, —SO2NRR′—NRR′, ═N—OR, ═N—NRR′, —C(═NR)—NRR′, —NR—NRR′, —(R)N—C(═NR)—NRR′, O←NR—, >C═NR, —(CH2)n—NR—COR′, —(CH2)n—CO—NRR′, —O—(CH2)n—OR, —O—(CH2)n—O—(CH2)n—R, —PRR′, —OPO3RR′, -PO2HR and n is an integer from 1 to 6 —PO3RR′, wherein R and R′ each independently is H, hydrocarbyl or heterocyclyl, R′ is optionally a residue of an RGD-containing peptide or a non-peptidic compound that mimics a peptide and has the RGD motif, or R and R′ together with the N atom to which they are attached form a 5-7 membered saturated ring optionally containing a further heteroatom selected from the group consisting of O, S and N, wherein the further N atom is optionally substituted, and R″ is H, a cation, hydrocarbyl or heterocyclyl; (d) C1-C25 hydrocarbyl substituted by one or more functional groups selected from the group consisting of positively charged groups, negatively charged groups, basic groups that are converted to positively charged groups under physiological conditions selected from the group consisting of —NRR′, —C(═NR)—NR′R″, —NR—NR′R″, —(R)N—C(═NR)—NR′R″, O←NRR′—, and >C═NR, wherein R, R′ and R″ each independently is H, optionally substituted hydrocarbyl or heterocyclyl, or two of R, R′ and R″ together with the N atom to which they are attached form a 3-7 membered saturated ring, optionally containing one or more heteroatoms selected from the group consisting of O, S or N, and optionally further substituted at the additional N atom, or the basic group is an N-containing heteroaromatic radical selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrimidyl, 1,2,4-triazinyl, 1,3,5-triazinyl or purinyl, and acidic groups that are converted to negatively charged groups under physiological conditions selected from the group consisting of COOH, COSH, SO3H, and PO3H2, or a salt thereof; (e) C1-C25 hydrocarbyl containing one or more heteroatoms and/or one or more carbocyclic or heterocyclic moieties; (f) C1-C25 hydrocarbyl containing one or more heteroatoms and/or one or more carbocyclic or heterocyclic moieties and substituted by one or more functional groups as defined in (c) and (d) above; (g) C1-C25 hydrocarbyl substituted by an amino acid residue, an RGD-containing peptide, a protein, a monosaccharide, an oligosaccharide, a polysaccharide, or a polydentate ligand and its chelating complexes with metals; or (h) a residue of an amino acid, an RGD-containing peptide or a non-peptidic compound that mimics a peptide and has the RGD motif, a protein, a monosaccharide, an oligosaccharide, a polysaccharide; or a polydentate ligand and its chelating complexes with metals; R8 is optionally H+ or a cation R+10 when R1, R′2 and R6 each independently is Y—R8; R+10 is a metal cation, an ammonium group or an organic cation derived from an amine or from a N-containing group selected from the group consisting of ammonium, hydrazinium, ammoniumoxy, iminium, amidinium or guanidinium; A− is a physiologically acceptable anion; m is 0 or 1; Hal is a halogen selected from fluoro, chloro, bromo or iodo; the dotted line at positions 7-8 represents an optional double bond; and pharmaceutically acceptable salts and optical isomers thereof; wherein said carbocyclic moiety is a saturated or partially unsaturated monocyclic or polycyclic compound containing only carbon atoms in the ring(s); said heterocyclic moiety or said heterocyclyl is a radical derived from a mono- or poly-cyclic heteroaromatic ring containing one to three O, S and/or N heteroatoms, selected from the group consisting of pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, quinolinyl, pyrimidinyl, 1,3,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzofuryl, isobenzofuryl, indolyl, imidazo[1,2-a]pyridyl, benzimidazolyl, benzthiazolyl and benzoxazolyl; and wherein said carbocyclic and heterocyclic moieties are optionally substituted by one or more radicals selected from the group consisting of halogen, C6-C14 aryl, C1-C25 alkyl, nitro, OR, SR, —COR, —COOR, —SO3R, —SO2R, —NHSO2R, —NRR′, (CH2)—NR—COR′ and —(CH2)—CO—NRR′; and wherein said chlorophyll or bacteriochlorophyll contains at least one RGD-containing peptide or a non-peptidic compound that mimics a peptide and has the RGD motif. |
