1,Phenanthroline forms a stable complex with Fe(II) ion called ferroin, which is used as an indicator in Fe(II) salt titrations. Ferroin is also. Structure, properties, spectra, suppliers and links for: phenanthroline, 1,Phenanthroline [ACD/Index Name] [ACD/IUPAC Name]. preferably any one of embodiments 1, 2 and 10, wherein ALK and ALK’ are both propylene, moetiy is typically an antagonist; if under such conditions the second targeting moiety is Tris(4,7-diphenyl- 1,phenanthroline)ruthenium( II).
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The conjugate of embodiment 76, wherein the glycoside is a N- glycoside, C-glycoside, O-gylcoside or an S-glycoside, preferably the glycoside is N- glycoside. In some embodiments, the activated sulfonic acid group is sulfonylchloride with chloride as leaving group. The conjugate of any one phenantroline embodiments 1 to 70, wherein moeetiy second targeting moiety is selected from the group comprising an antibody, an antigen-binding antibody fragment, a camelid heavy chain IgG hcIgGa cartilaginous fish IgNAR antibody, a protein scaffold, a target-binding peptide, a peptide nucleic acid PNAa target-binding polypeptide or protein, a target binding nucleic acid molecule, a carbohydrate, a lipid and a target-binding small molecule.
Futhermore, these and other problems are solved moety the following embodiments. The conjugate of embodiment 79, wherein the disease is a disease involving a target targeted by the first targeting moiety TM1 or by the scond targeting moiety TM2, preferably the disease is one involving neurotensin receptor, more preferably the disease is a disease involving neurotensin receptor 1.
Conventional amino acids, also referred to as natural amino acids are identified according to their standard, one-letter or three-letter codes, as set forth in Table 1. The conjugate of any one of embodiments 93 to 99, wherein Effector is a radionuclide, wherein preferably the radionuclide is covalently bound by Acceptor, wherein Acceptor comprises an aromatic moiety, wherein the aromatic moiety is selected from the group comprising indole and benzene, preferably benzene is substituted with at least one heteroatom, wherein the heteroatom is selected from the group comprising O, N and S.
Preferred embodiments may be taken from the attached dependent claims. A still further problem underlying the present invention is the provision of a method for the identification of a subject, wherein the subject is likely to respond or likely not to respond to a treatment of a disease, a method for the selection of a subject from a group of subjects, wherein the subject is likely to respond or likely not to respond to a treatment of a disease.
These neurotensin moetig are transmembrane receptors that bind the neurotransmitter neurotensin Vincent et al, Trends Pharmacol. In an embodiment and as preferably used herein, an indication is a medical indication. Selected synthetic precursors for the adapter moieties for this application are in either commercially available and also referred to as cross-linkers, or can be prepared by a person skilled in the art by routine measure.
In a preferred embodiment the linkage and the type of linkage is as defined herein. In an embodiment the cartilaginous fish is shark. In an embodiment and as preferably used herein, an amine linkage is a linkage, wherein an N atom is bound to a C atom -N-C. Also, a problem underlying the present invention is the provision of a pharmaceutical composition containing a compound having the characteristics as outlined above.
The conjugate of any one of embodiments 1 to 78, for use in a method for the treatment of a disease. The conjugate of any one of embodiments 1 to 78, for use in a method for the diagnosis of a disease.
A non-limiting list of linkages as preferably used in connection with the conjugate of phenanthrroline invention and the characteristic type of atom arrangement is presented Table 3. The preparation of 56 is described in Example 5A. In an embodiment the conjugate of the invention is an antagonist to NTRl.
O-Phenanthroline | C12H8N2 – PubChem
USA, thus suggesting the use of target molecule agonists rather than target molecule antagonists. A generic formula of a preferred embodiment of an adapter moiety is as follows:.
In accordance with the function of an adapter moiety in a conjugate of the invention, the backbone of such adaptor moiety can, in principle, be quite diverse as long as such backbone of the adaptor moiety does not interfere with the synthesis and use, respectively, of the conjugate of the invention.
Theoretically, a high affinity of the compound as such, i.
Phenanthroline – Wikipedia
The conjugate of any one of embodiments 95 to 97, wherein Effector is a therapeutically active agent. The conjugate according to any one of embodiments 1 and 2, wherein. In an embodiment the number of covalent bonds between the first targeting moiety TM1 and the second targeting moiety TM2 is 1. In an embodiment and as preferably used herein, the term “halogen” or “halogenide” means each and individually any of F, CI, Br, I and At. Binding and pharmacological studies demonstrate that this receptor binds neurotensin as well as several other ligands already described for NTRl.
The conjugate of any one of embodiments 2 to 71, wherein the Effector is a diagnostically active nuclide or a therapeutically active nuclide, wherein the diagnostically active nuclide and the therapeutically active radionuclide is individually and independently selected from the group comprising m In, 99m Tc, 67 Ga, 52 Fe, 68 Ga, 72 As, m In, 97 Ru, Pb, 62 Cu, “Cu, 51 Cr, 52m Mn, Gd, 64 Cu, 89 Zr, and ,77 Lu, ,86 Re, 90 Y, 67 Cu, 68 Ga, 69 Er.
In an embodiment and as preferably used herein, C 3 -C 6 alkyl means each and individually any of n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2- methyl-butyl, 3 -methyl-butyl, 3-pentyl, 3-methyl-butyl, 2-methyl-butyl, 2,2- dimethylpropyl, n-hexyl, 2-hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 3- hexyl, 2-ethyl-butyl, 2-methyl-pentyl, 2,2-dimethyl-butyl, 3, 3 -dimethyl-butyl, 3-methyl- pentyl, 4-methyl-pentyl, 2,3-dimethyl-butyl, 3-methyl-pentyl, 2-methyl-pentyl.
Such moieties are the first target moiety TM1, the first adapter moiety AD1, the linker moiety LM, the second adaptor moiety AD2, the second targeting moiety TM2, the third adapter moiety AD3 and the effector moiety EM, as well as building block moiety X, a building block moiety Z and building block moiety Y.
In another embodiment of the conjugate of the invention the conjugate comprises, in terms of an adapter moiety, only a first adapter moiety ADl and a second adapter moiety AD2. In an embodiment and as preferably used herein, C3-C 8 heterocycle refers to an aromatic or non-aromatic C 3 -C 8 carbocycle in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N.
The conjugate of any one of embodiments 79 to 91, wherein the method comprises the administration of a diagnostically effective amount of the compound to a subject, preferably to a mammal, wherein the mammal is selected from the group comprising man, companion animals, pets and livestock, more preferably the subject is selected from the group comprising man, dog, cat, horse and cow, and most preferably the subject is a human being.
More preferably such discrimination or distinction forms the basis for said diagnosis and diagnosing, respectively. Phenanthroline may be prepared by two successive Skraup reactions of glycerol with o -phenylenediaminecatalyzed by sulfuric acidand an oxidizing agent, traditionally aqueous arsenic acid or nitrobenzene.
It is, however, well known that the radionuclide chemistry and associated linkages are crucial particularly with respect to the attachment to the compound of an effector which provides the signal needed for diagnosis or which provides the therapeutically effective activity. S45S60S The conjugate of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8 and 9, wherein R 3R 4 and R 5 are each and independently methyl under the proviso that one of R 3R 4 and R 5 is of the following formula 3: The rationale behind this understanding in the art is that an effective in vivo diagnosis and therapy, particular in case such diagnosis and therapy makes use of a radiolabel such as a radionuclide attached to a compound having an affinity to a target molecule such as a receptor, requires that such compound shows good internalization properties leading to a high in vivo accumulation and retention of the compound and thus of the effector in the tissue and cells, respectively, expressing the target molecule.
In contrast thereto, an antagonist to NTRl as the conjugate of the invention counteracts the effect of an agonist to NTRl and is preferably not internalized into NTRl expressing cells.
In the central nervous system, expression has been found in the diagonal band of Broca, medial septal nucleus, nucleus basalis magnocellularis, suprachiasmatic nucleus, supramammillary area, substantia nigra and ventral tegmental area.
A carbocyclic aromatic group or a heterocyclic aromatic group can be unsubstituted or substituted with one or more groups including, but not limited to, – Q- C 8 alkyl, [ C!