10 PHENANTHROLINE MOETIY PDF

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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Neurotensin was first isolated from extracts of bovine hypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthetized rats Carraway et al, J. Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens.

It induces a variety of effects, including analgesia, hypothermia and increased locomotor activity. It moeiy also involved in regulation of dopamine pathways.

In the periphery, neurotensin is found in endocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction Friry et al. Neurotensin is bound by neurotensin mmoetiy.

phenanthroline | C12H8N2 | ChemSpider

Three neurotensin receptors are known, namely neurotensin receptor 1, also referred to as NTRl, neurotensin receptor 2, also referred to as NTR2, and neurotensin receptor 3, also referred to as NTR3. These neurotensin receptors are transmembrane receptors that bind the neurotransmitter neurotensin Vincent et al, Trends Pharmacol.

The neurotensin receptor 1 NTRl was cloned in from rat brain and found to act as a high affinity, phfnanthroline insensitive receptor for neurotensin Tanaka et al, Neuron,4, The affinity of neurotensin phenanthrolin the receptor could be decreased by both sodium ions and guanosine triphosphate GTP Vincent et al, Trends Pharmacol.

NTRl is expressed predominantly in the central nervous system and intestine phenqnthroline muscle, mucosa and nerve 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.

The receptor is also expressed in the dorsal root ganglion neurones of the spinal cord. The predominant response upon activation of the receptor by neurotensin is activation of phospholipase C, causing an increase in intracellular calcium levels.

The receptor can also stimulate cAMP formation, MAP kinase activation and the induction of growth related genes, such as krox Vincent et al. Dermatol, The protein encoded by this gene belongs to the G protein-coupled receptor family that phenanthrolne a phosphatidylinositol-calcium second messenger system.

Binding and pharmacological studies demonstrate that this receptor binds neurotensin as well as several other ligands already described for NTRl. However, unlike NTRl, NTR2 recognizes, with high affinity, levocabastine, a histamine HI receptor antagonist previously shown to compete with neurotensin for low-affinity binding sites in the central nervous system.

These activities suggest that this receptor may be of physiological importance and that a natural agonist for the receptor may exist.

Phenanthroline

Neurotensin receptor 3 NTR3 is a non-G-protein coupled receptor. NTR3 is a sorting protein involved in cellular trafficking and neuropeptide signalling. Apart from the central nervous system, NTR1 is highly expressed in a mammalian body and a human body in particular on several neoplastic cells in several tumor indications, whereas the expression of NTR1 in most other tissues of the mammalian and the human body is either not existent or low.

Only for colon weak or moderate expression under physiological conditions is described. The following table summarizes the expression of NTR1 as described in the prior art indicating the tissue, degree of expression, detection method and the respective references.

Phenanthroline – Wikipedia

These NTR1 expressing tumor indications include but are not limited to ductal pancreatic adenocarcinoma, small cell phenanthrolins cancer, prostate cancer, colorectal cancer, breast cancer, meningioma, Ewing’s sarcoma, pleural mesothelioma, head and neck phenxnthroline, non-small cell lung cancer, gastrointestinal stromal tumors, uterine leiomyoma and phenanthrolinf T-cell moeiy.

A preferred group of NTR1 expressing tumor indications are ductal pancreatic adenocarcinoma, moegiy cell lung cancer, prostate cancer, colorectal cancer, breast cancer, meningioma and Ewing’s moetiyy. Agonists and antagonists binding to NTR1 have been described in the prior art.

Most of these agonist peptides are derivatives of neurotensin, its C-terminal eight amino acids. US discloses metabolically protected analogs of neurotensin.

US discloses a synthetic tridecapeptide [Gln 4 ]-neurotensin having hormonal activity. US discloses neurotensin mimetics as central nervous system agents. These peptides as well as the further ligands of NTR1, namely neuromedin N and xenin, can be used for imaging purposes and therapeutic purposes. Typically, the agonist carries a therapeutically or diagnostically active effector such as a chelated metal label and more specifically a chelated radiolabel suitable for therapy and diagnosis, respectively.

The effector bearing agonist binds to the receptor and, upon binding to the receptor, the effector bearing agonist is internalized by the receptor and the effector bearing agonist thus trapped in the target cell.

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It will be understood by a person skilled in the art that such trapping of the effector bearing agonist may go along with the release of the effector from the agonist. Such metabolic conversion may occur through the metabolism and enzymatic activities in particular of the organism to which the effector bearing agonist has been administered and more specifically the metabolism of the cell and tissue, respectively, into which the effector bearing agonist has been internalized.

Imaging,36, Biol,28, ; Garcia-Garayoa et al, J.

Biol,33, ; Garcia-Garayoa et al, Eur. Imaging,36, ; Bergmann et al, Nucl. Biol,29, ; Bruehlmeier et al, Nucl. Biol,29, ; Blauenstein et al, Cancer Biother. Imaging,34,NT analogs Alshoukr et al, Bioconjug. Imaging,30, ; and Janssen et ah, Cancer Biother. It was found that most neurotensin-derived metal labeled peptides have a very short circulation half-life due to rapid renal clearance as often observed for peptidic molecules.

Phenxnthroline, tumor accumulation is rather limited for such molecules.

These small molecule compounds and SR in particular, however, cross the blood-brain barrier and are thus suitable neither for the radionuclide therapy of tumors nor for the radioactive diagnosis of tumors and imaging in particular, whereby the tumors are preferably those expressing NTR1, since irradiation of the central nervous system or any other non-radioactive cell-killing effect may have detrimental effects on the patient.

Additionally, the radiolabeling of these compounds is difficult. Even more difficult is designing and synthesizing a radiolabeled derivative of these compounds without diminishing or destroying the original and desired high NTR1 affinity. It is imperative that the compound has appropriate in vivo targeting and pharmacokinetic properties. It is, however, well known that the radionuclide moeetiy 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.

Such effector can be attached to the compound either directly or through a connecting moiety. In case the effector is a radiolabel and the radiolabel is attached to the compound by a connecting moiety such as, for example, a chelator, the labeling of such a connecting phenanthorline and chelator, respectively, is a further crucial step in the identification of a suitable compound Fritzberg et al, J.

Hence the type of radionuclide, the type phemanthroline compound which mediates target binding, and the method used for linking them to one another may have unpredictable effects on the properties of the radiolabeled version of the compound. Theoretically, a high affinity of the compound as such, i.

However, it is well known that the affinity and receptor specificity of the compound as such, i. Therefore, an optimal compound and even more so a radiolabeled version thereof suitable for diagnosis and therapy, respectively, of a disease is a matter of luck rather than of a rational and predictable development process.

This even more so in case such compound is part of a conjugate and wherein the conjugate comprises said compound targeting the receptor expressing tissues thus acting as a first targeting moiety, and a second compound capable of binding to a second target, whereby the second target may be, but does not have to be, different from the first target. 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 phenwnthroline 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.

Also, a problem underlying the present invention is the phenanthrolline of a pharmaceutical composition containing a compound having the characteristics as outlined above.

Furthermore, a problem underlying the present invention is the provision of a kit which is suitable for use in phenannthroline of the above methods. These and other problems are solved by the subject matter of the attached independent claims. Preferred embodiments may be taken from the attached dependent claims. Futhermore, these and other problems phenatnhroline solved by the following embodiments. TM1 is a first targeting moiety, wherein the first targeting moiety is capable of binding to a first target.

TM2 is a second targeting moiety, wherein the second targeting moiety is capable of binding to a second target. R 1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3. R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 – Cg cycloalkylmethyl, halogen, nitro and trifluoromethyl.

R 3R 4 and R 5 are each and independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl under the proviso phenanthrolnie one of R 3R 4 and R 5 is of the following phenanthhroline 3.

R 6 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and. The conjugate of embodiment 1, wherein the conjugate comprises an Effector moiety, wherein the Effector pjenanthroline comprises or is capable of comprising an Effector, wherein lhenanthroline Effector is selected from the group comprising a diagnostically active agent, a therapeutically active agent and a combination thereof.

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The conjugate of any one of embodiments 1 and 2, wherein the R 1 phenantjroline methyl. The conjugate of any one of embodiments 1, 2 and 3, wherein AA- COOH is an amino acid selected from the phemanthroline consisting of 2-aminoadamantane carboxylic acid and phenatnhroline.

The conjugate of any one of embodiments 1, 2, 3, 4, 5 and 6, preferably any one of embodiments 1 and 2, wherein R is isopropyl. Phenanthrolime conjugate of any one metiy embodiments 1, 2, 3, 4, 5, 6 and 7, preferably any one of embodiments 1 and 2, wherein R3, R4 and R5 are each and independently selected from the group consisting of hydrogen and methyl under the proviso that one of R3, R4 and R5 is of the following formula 3.

R 6 is selected from the group consisting of hydrogen and C! The conjugate of embodiment 8, wherein R 6 is selected from the group consisting of hydrogen and methyl. 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 phenanhtroline independently methyl under the proviso that one of R mooetiyR 4 and R 5 is of the following formula 3: R 6 is selected from the group consisting of hydrogen and phenaanthroline.

AA-COOH is an amino acid selected from the group consisting of 2-amino adamantane carboxylic acid and cyclohexylglycine; and. The conjugate of any one of embodiments 1, 2 and 12, wherein. R 3R 4 and R 5 are each and independently selected from the group consisting of hydrogen and methyl under the proviso that one of R 3R 4 and R 5 is of the following formula 3: AA-COOH is phnanthroline amino acid selected from the moetyi consisting of 2-amino adamantane carboxylic acid and cyclohexylglycine.

R 3R 4 and R 5 are each and independently selected from the group consisting of hydrogen and methyl under the proviso that one of R 3Phenanthrolins 4 and R 5 is of the following formula The conjugate of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13 and 14, preferably any one of embodiments 12, 13 and 14, 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 moftiy 3: The conjugate of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, preferably of any one of embodiments 12, 13, 14 and 15, wherein. The conjugate according to any one of embodiments 1 and 2, wherein. R 3R 4 and R 5 are each and independently selected from the group consisting of hydrogen and methyl under the proviso that one of R 3Noetiy 4 and R 5 is of the following formula 3.

R 6 is selected from the group consisting of hydrogen and methyl; and. The conjugate of any one of embodiments 1 to 18, wherein the first targeting moiety is selected from the group consisting of a compound of formula 4a compound of formula 5 and a compound of formula 6wherein.

The conjugate of any one of embodiments 1 to 19, wherein the second targeting moiety and the first targeting moiety is a targeting moiety as defined in any one of embodiments 1 to The conjugate of any one of embodiments 20 and 21wherein the first targeting moiety is a compound of formula 4.

The conjugate of any one of embodiments 20 and 21, wherein the first targeting moiety is a com ound of formula 4. The conjugate of any one of embodiments 1 to 25, preferably any one of embodiments 20 to 25, wherein the first targeting moiety and the second targeting moiety are separated by 4 to covalent bonds, preferably 5 to covalent bonds, more preferably 10 to 40 covalent bonds.

The conjugate of any one of embodiments 1 to 26, preferably any one of embodiments 20 to 26, wherein the linker moiety LM is of general formula:. The conjugate of embodiment 27, wherein building block moiety [X] a is phenanthfoline to an adjacent moiety through a linkage, wherein the mostiy is individually and independently selected from the group comprising an amide linkage, a urea linkage, a carbamate linkage, an ester linkage, an ether linkage, a thioether linkage and a disulfide linkage, and wherein the adjacent moiety is selected from the group comprising branching moiety [Y], building block moiety [Z] bsecond adapter moiety AD2, second targeting moiety TM2, first adapter moiety AD1 and first targeting moiety TM1.

The conjugate of any one of embodiment 27 and 28, wherein the building block X is of eneral formula.