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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Gallium 68 PSMA-11


str1

Gallium 68 PSMA-11

FDA APPROVED, 12/1/2020, Gallium 68 PSMA-11

For detection and localization of prostate cancer
Press Release
Drug Trials Snapshot

Figure 3: Different structures of the different prostate-specific membrane antigen agents
Theranostics 10: 0001 image No. 001

Chemical structure of 18F-labeled radiotracers. [18F]DCFPyL (A), [18F]PSMA-1007 (B), [18F]CTT1057 (C), (D) [18F]JK-PSMA-7 and (E) [18F]AIF-PSMA-11. The urea backbone of (A), (B), (D) and (E) is marked in blue, while the phosphoramidate of [18F]CTT1057 in (C) is highlighted in orange. Modified from Behr et al. [32], © by the Society of Nuclear Medicine and Molecular Imaging, Inc.

PSMA-11, also known as HBED-CC-PSMA or Psma-hbed-CC, is used to make gallium Ga 68-labeled PSMA-11, which has potential use as a tracer for PSMA-expressing tumors during positron emission tomography (PET). Upon intravenous administration of gallium Ga 68-labeled PSMA-11, the Glu-urea-Lys(Ahx) moiety targets and binds to PSMA-expressing tumor cells. Upon internalization, PSMA-expressing tumor cells can be detected during PET imaging. PSMA, a tumor-associated antigen and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells

img

Name: PSMA-11
CAS#: 1366302-52-4
Chemical Formula: C44H62N6O17
Exact Mass: 946.4171

(3S,7S)-22-(3-(((2-((5-(2-Carboxyethyl)-2-hydroxybenzyl)(carboxymethyl)amino)ethyl)(carboxymethyl)amino)methyl)-4-hydroxyphenyl)-5,13,20-trioxo-4,6,12,19-tetraazadocosane-1,3,7-tricarboxylic acid

The Food and Drug Administration (FDA) has approved Gallium 68 PSMA-11 (Ga 68 PSMA-11), the first drug for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer.

Ga 68 PSMA-11, a radioactive diagnostic agent, is indicated for patients with suspected prostate cancer metastasis who are potentially curable by surgery or radiation therapy. It is also indicated for patients with suspected prostate cancer recurrence based on elevated serum prostate-specific antigen (PSA) levels. 

The approval was based on efficacy and safety data from 2 prospective clinical trials (Trial 1 and 2) with a total of 960 men with prostate cancer who each received 1 injection of Ga 68 PSMA-11. Trial 1 included 325 patients with biopsy-proven prostate cancer who underwent PET/CT or PET/MRI scans performed with Ga 68 PSMA-11. Results from the study showed that positive readings in the pelvic lymph nodes on Ga 68 PSMA-11 PET were associated with a clinically important rate of metastatic cancer confirmed by surgical pathology in those who proceeded to surgery. 

In Trial 2, 635 patients with rising serum PSA levels after prostate surgery or radiotherapy received a single Ga 68 PSMA-11 PET/CT scan or PET/MR scan. Findings demonstrated that 74% of patients had at least 1 positive lesion detected by Ga 68 PSMA-11 PET, and local recurrence or metastasis of prostate cancer was confirmed in 91% of cases.

This is the first drug approved for PET imaging of prostate-specific membrane antigen positive lesions in men with prostate cancer.

REF

REFERENCES

1: Meißner S, Janssen JC, Prasad V, Brenner W, Diederichs G, Hamm B, Hofheinz F, Makowski MR. Potential of asphericity as a novel diagnostic parameter in the evaluation of patients with (68)Ga-PSMA-HBED-CC PET-positive prostate cancer lesions. EJNMMI Res. 2017 Oct 23;7(1):85. doi: 10.1186/s13550-017-0333-9. PubMed PMID: 29058157; PubMed Central PMCID: PMC5651532.

2: Verburg FA, Pfister D, Drude NI, Mottaghy FM, Behrendt F. PSA levels, PSA doubling time, Gleason score and prior therapy cannot predict measured uptake of [(68)Ga]PSMA-HBED-CC lesion uptake in recurrent/metastatic prostate cancer. Nuklearmedizin. 2017 Oct 18;56(6). doi: 10.3413/Nukmed-0917-17-07. [Epub ahead of print] PubMed PMID: 29044297.

3: Amor-Coarasa A, Kelly JM, Gruca M, Nikolopoulou A, Vallabhajosula S, Babich JW. Continuation of comprehensive quality control of the itG (68)Ge/(68)Ga generator and production of (68)Ga-DOTATOC and (68)Ga-PSMA-HBED-CC for clinical research studies. Nucl Med Biol. 2017 Oct;53:37-39. doi: 10.1016/j.nucmedbio.2017.07.006. Epub 2017 Jul 14. PubMed PMID: 28803001.

4: Janssen JC, Woythal N, Meißner S, Prasad V, Brenner W, Diederichs G, Hamm B, Makowski MR. [(68)Ga]PSMA-HBED-CC Uptake in Osteolytic, Osteoblastic, and Bone Marrow Metastases of Prostate Cancer Patients. Mol Imaging Biol. 2017 Dec;19(6):933-943. doi: 10.1007/s11307-017-1101-y. PubMed PMID: 28707038.

5: Damle NA, Tripathi M, Chakraborty PS, Sahoo MK, Bal C, Aggarwal S, Arora G, Kumar P, Kumar R, Gupta R. Unusual Uptake of Prostate Specific Tracer (68)Ga-PSMA-HBED-CC in a Benign Thyroid Nodule. Nucl Med Mol Imaging. 2016 Dec;50(4):344-347. Epub 2016 Mar 22. PubMed PMID: 27994690; PubMed Central PMCID: PMC5135692.

6: Behrendt F, Krohn T, Mottaghy F, Verburg FA. [(68)Ga]PSMA-HBED-CC PET/CT to differentiate between diffuse bone metastases of prostate cancer and osteopoikilosis. Nuklearmedizin. 2016 Dec 6;55(6):N64-N65. PubMed PMID: 27922151.

7: Krohn T, Birmes A, Winz OH, Drude NI, Mottaghy FM, Behrendt FF, Verburg FA. The reconstruction algorithm used for [(68)Ga]PSMA-HBED-CC PET/CT reconstruction significantly influences the number of detected lymph node metastases and coeliac ganglia. Eur J Nucl Med Mol Imaging. 2017 Apr;44(4):662-669. doi: 10.1007/s00259-016-3571-6. Epub 2016 Nov 29. PubMed PMID: 27900518.

8: Berliner C, Tienken M, Frenzel T, Kobayashi Y, Helberg A, Kirchner U, Klutmann S, Beyersdorff D, Budäus L, Wester HJ, Mester J, Bannas P. Detection rate of PET/CT in patients with biochemical relapse of prostate cancer using [(68)Ga]PSMA I&T and comparison with published data of [(68)Ga]PSMA HBED-CC. Eur J Nucl Med Mol Imaging. 2017 Apr;44(4):670-677. doi: 10.1007/s00259-016-3572-5. Epub 2016 Nov 28. PubMed PMID: 27896369.

9: Sathekge M, Lengana T, Modiselle M, Vorster M, Zeevaart J, Maes A, Ebenhan T, Van de Wiele C. (68)Ga-PSMA-HBED-CC PET imaging in breast carcinoma patients. Eur J Nucl Med Mol Imaging. 2017 Apr;44(4):689-694. doi: 10.1007/s00259-016-3563-6. Epub 2016 Nov 8. PubMed PMID: 27822700; PubMed Central PMCID: PMC5323468.

10: Rauscher I, Maurer T, Beer AJ, Graner FP, Haller B, Weirich G, Doherty A, Gschwend JE, Schwaiger M, Eiber M. Value of 68Ga-PSMA HBED-CC PET for the Assessment of Lymph Node Metastases in Prostate Cancer Patients with Biochemical Recurrence: Comparison with Histopathology After Salvage Lymphadenectomy. J Nucl Med. 2016 Nov;57(11):1713-1719. Epub 2016 Jun 3. PubMed PMID: 27261524.

11: Verburg FA, Behrendt FF, Mottaghy FM, Pfister D, Steib F, Knuechel R. Strong [(68)Ga]PSMA-HBED-CC accumulation in non-cancerous prostate tissue surrounding a PSMA-negative prostate carcinoma recurrence. Nuklearmedizin. 2016 Sep 26;55(5):N44-5. PubMed PMID: 27668299.

12: Kanthan GL, Izard MA, Emmett L, Hsiao E, Schembri GP. Schwannoma Showing Avid Uptake on 68Ga-PSMA-HBED-CC PET/CT. Clin Nucl Med. 2016 Sep;41(9):703-4. doi: 10.1097/RLU.0000000000001281. PubMed PMID: 27405039.

13: Noto B, Vrachimis A, Schäfers M, Stegger L, Rahbar K. Subacute Stroke Mimicking Cerebral Metastasis in 68Ga-PSMA-HBED-CC PET/CT. Clin Nucl Med. 2016 Oct;41(10):e449-51. doi: 10.1097/RLU.0000000000001291. PubMed PMID: 27355852.

14: Pfob CH, Ziegler S, Graner FP, Köhner M, Schachoff S, Blechert B, Wester HJ, Scheidhauer K, Schwaiger M, Maurer T, Eiber M. Biodistribution and radiation dosimetry of (68)Ga-PSMA HBED CC-a PSMA specific probe for PET imaging of prostate cancer. Eur J Nucl Med Mol Imaging. 2016 Oct;43(11):1962-70. doi: 10.1007/s00259-016-3424-3. Epub 2016 May 20. PubMed PMID: 27207281.

15: Amor-Coarasa A, Schoendorf M, Meckel M, Vallabhajosula S, Babich JW. Comprehensive Quality Control of the ITG 68Ge/68Ga Generator and Synthesis of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for Clinical Imaging. J Nucl Med. 2016 Sep;57(9):1402-5. doi: 10.2967/jnumed.115.171249. Epub 2016 Apr 21. PubMed PMID: 27103024.

16: Prasad V, Steffen IG, Diederichs G, Makowski MR, Wust P, Brenner W. Biodistribution of [(68)Ga]PSMA-HBED-CC in Patients with Prostate Cancer: Characterization of Uptake in Normal Organs and Tumour Lesions. Mol Imaging Biol. 2016 Jun;18(3):428-36. doi: 10.1007/s11307-016-0945-x. PubMed PMID: 27038316.

17: Pfister D, Porres D, Heidenreich A, Heidegger I, Knuechel R, Steib F, Behrendt FF, Verburg FA. Detection of recurrent prostate cancer lesions before salvage lymphadenectomy is more accurate with (68)Ga-PSMA-HBED-CC than with (18)F-Fluoroethylcholine PET/CT. Eur J Nucl Med Mol Imaging. 2016 Jul;43(8):1410-7. doi: 10.1007/s00259-016-3366-9. Epub 2016 Mar 19. PubMed PMID: 26993315.

18: Kanthan GL, Coyle L, Kneebone A, Schembri GP, Hsiao E. Follicular Lymphoma Showing Avid Uptake on 68Ga PSMA-HBED-CC PET/CT. Clin Nucl Med. 2016 Jun;41(6):500-1. doi: 10.1097/RLU.0000000000001169. PubMed PMID: 26914565.

19: Kanthan GL, Hsiao E, Kneebone A, Eade T, Schembri GP. Desmoid Tumor Showing Intense Uptake on 68Ga PSMA-HBED-CC PET/CT. Clin Nucl Med. 2016 Jun;41(6):508-9. doi: 10.1097/RLU.0000000000001192. PubMed PMID: 26909712.

20: Eiber M, Weirich G, Holzapfel K, Souvatzoglou M, Haller B, Rauscher I, Beer AJ, Wester HJ, Gschwend J, Schwaiger M, Maurer T. Simultaneous (68)Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer. Eur Urol. 2016 Nov;70(5):829-836. doi: 10.1016/j.eururo.2015.12.053. Epub 2016 Jan 18. PubMed PMID: 26795686.

//////////Gallium 68 PSMA-11,  FDA 2020, 2020 APPROVALS, RADIO ACTIVE

Borofalan (10B)


Boronophenylalanine B-10.png
ChemSpider 2D Image | Borofalan (10B) | C9H1210BNO4

Borofalan (10B), ボロファラン (10B), 硼[10B]法仑

APPROVED JAPAN, 2020/3/25, Steboronine

Antineoplastic, Diagnostic aid, Radioactive agent

(2S)-2-amino-3-(4-(10B)dihydroxy(10B)phenyl)propanoic acid

FormulaC9H12BNO4
CAS80994-59-8
Mol weight209.0069
  • 4-(Borono-10B)-L-phenylalanine
  • (10B)-4-Borono-L-phenylalanine
  • Borofalan (10b)
  • L-(p-[10B]Boronophenyl)alanine
  • L-4-[10B]Boronophenylalanine
    • p-[10B]Borono-L-phenylalanine
  • L-Phenylalanine, 4-borono-10B-
    Marketed Head and neck cancer
  • Originator Stella Pharma
  • Developer Osaka University; Stella Pharma; Sumitomo Heavy Industries
  • Class Antineoplastics; Borates; Propionic acids; Radiopharmaceuticals
  • Mechanism of Action Ionising radiation emitters
  • Phase IIGlioma
  • Phase I Haemangiosarcoma; Malignant melanoma

Borofalan (10B)

4-[(10B)Borono]-L-phenylalanine

C9H1210BNO4 : 208.21
[80994-59-8]

With the development of atomic science, radiation therapy such as cobalt hexahydrate, linear accelerator, and electron beam has become one of the main methods of cancer treatment. However, traditional photon or electron therapy is limited by the physical conditions of the radiation itself. While killing the tumor cells, it also causes damage to a large number of normal tissues on the beam path. In addition, due to the sensitivity of tumor cells to radiation, traditional radiation therapy For the more radiation-resistant malignant tumors (such as: glioblastoma multiforme, melanoma), the treatment effect is often poor.

In order to reduce the radiation damage of normal tissues around the tumor, the concept of target treatment in chemotherapy has been applied to radiation therapy; and for tumor cells with high radiation resistance, it is currently actively developing with high relative biological effects (relative Biological effectiveness, RBE) radiation sources, such as proton therapy, heavy particle therapy, neutron capture therapy. Among them, neutron capture therapy combines the above two concepts, such as boron neutron capture therapy, by the specific agglomeration of boron-containing drugs in tumor cells, combined with precise neutron beam regulation, providing better radiation than traditional radiation. Cancer treatment options.

Boron Neutron Capture Therapy (BNCT) is a high-capture cross-section of thermal neutrons using boron-containing ( 10 B) drugs, with 10 B(n,α) 7 Li neutron capture and nuclear splitting reactions. Two heavy charged particles of 4 He and 7 Li are produced. The average energy of the two charged particles is about 2.33 MeV, which has high linear energy transfer (LET) and short range characteristics. The linear energy transfer and range of α particles are 150 keV/μm and 8 μm, respectively, while the 7 Li heavy particles are For 175 keV/μm, 5 μm, the total range of the two particles is equivalent to a cell size, so the radiation damage caused to the organism can be limited to the cell level, when the boron-containing drug is selectively aggregated in the tumor cells, with appropriate The sub-radiation source can achieve the purpose of locally killing tumor cells without causing too much damage to normal tissues.

Since the effectiveness of boron neutron capture therapy depends on the concentration of boron-containing drugs in the tumor cell position and the number of thermal neutrons, it is also called binary cancer therapy; thus, in addition to the development of neutron sources, The development of boron-containing drugs plays an important role in the study of boron neutron capture therapy.

4-( 10 B)dihydroxyboryl-L-phenylalanine (4-( 10 B)borono-L-phenylalanine, L- 10 BPA) is currently known to be able to utilize boron neutron capture therapy (boron neutron capture therapy) , BNCT) An important boron-containing drug for the treatment of cancer.

Therefore, various synthetic methods of L-BPA have been developed. As shown in the following formula (A), the prior art L-BPA synthesis method includes two methods of forming a bond (a) and a bond (b):

Figure PCTCN2016094881-appb-000001

Among them, the method for synthesizing L-BPA by forming the bond (a) is to try to introduce a substituent containing a dihydroxylboryl group or a borono group into the skeleton of the phenylalanine, thereby the pair of the amide substituent. The position forms a carbon-boron bond to produce L-BPA.

J. Org. Chem. 1998, 63, 8019 discloses a method for the cross-coupling reaction of (S)-4-iodophenylalanine with a diboron compound by palladium-catalyzed amine end treatment. Amine-protected (S)-4-iodophenylalanine (eg (S)-N-tert-butoxycarbonyl-4-iodophenylalanine ((S)-N-Boc-4-) Iodophenylalanine)) is prepared by cross-coupling with a diboron compound such as bis(pinacolato diboron) to give (S)-N-tert-butoxycarbonyl-4-pentanoylboryl phenylalanine The amine-terminated (S)-4-boranyl ester phenylalanine of the acid ((S)-N-Boc-4-pinacolatoborono phenylalanine); afterwards, the protecting group on the amine end and the boronic end are removed. The above substituents complete the preparation of L-BPA.

However, since the selected 10 B-doped divaleryl diboron is not a commercially available compound, this method requires additional pretreatment of the preparation of the borating agent, resulting in a high process complexity and a long time consuming process. It is impossible to prepare a high yield of L-BPA. In addition, the carboxylic acid group of the protected (S)-4-iodophenylalanine at the amine end needs to be protected by a substituent to form a benzyl ester group to increase the process yield to 88%; however, The preparation of L-BPA in this manner also requires an additional step of deprotecting the carboxylic acid group, which in turn increases the process complexity of L-BPA.

Accordingly, the method provided in this document not only involves pre-treatment of the preparation of the borating agent, but also requires a large amount of process time and synthesis steps to complete the steps of protecting and deprotecting the carboxylic acid group, and is not advantageous as an industry. The main method of synthesizing L-BPA.

On the other hand, a method for synthesizing L-BPA by forming a bond (b) is a coupling reaction of an amino acid with a boron-containing benzyl fragment or a boron-containing benzaldehyde fragment. To synthesize L-BPA. Biosci. Biotech. Biochem. 1996, 60, 683 discloses an enantioselective synthesis of L-BPA which gives the hands of a cyclic ethers of boronic acid and L-proline The chiral derivatives from L-valine are subjected to a coupling reaction to produce L-BPA. However, this method requires the formation of a cyclic ether compound of boric acid from 4-boronobenzylbromide, followed by a coupling reaction with a chiral derivative of L-proline, and in the latter stage. The amino acid undergoes an undesired racemization in the synthesis step, so that the method requires an enzymatic resolution step to reduce the yield to obtain L-BPA having a certain optical purity.

Accordingly, the method provided in the literature still includes the steps of pretreatment of the preparation of the borating agent and post-treatment of the enzymatic resolution, so that the process involved in the method is complicated and takes a long time, and cannot be obtained. High yield of L-BPA.

In addition, L- 10 BPA (4-( 10 B)borono-L-phenylalanine, 4-( 10 B)dihydroxyboryl-L-phenylalanine) containing 10 boron is currently known to accumulate in tumor cells. The key factor is to use the thermal neutron beam to irradiate the boron element accumulated in the tumor cells to kill the tumor cells by capturing the high-energy particles generated by the reaction, thereby achieving the purpose of treating cancer. Therefore, 10 boron can promote the treatment of L- 10 BPA by boron neutron capture treatment.

However, the boron element present in nature contains about 19.9% of 10 boron and about 80.1% of 11 boron. Therefore, many researchers are still actively developing methods that can be applied to the synthesis of L-BPA, especially for the synthesis of 10- boron-rich L-BPA.

J.Org.Chem.1998,63,8019 additionally provides a method of synthesizing 10 boronated agents, since the method involves multiple steps, it is easy to greatly reduce the boron content of 10 10 boron enriched material in the manufacturing process. Therefore, the method provided in this document is not suitable for the synthesis of 10- boron-rich L-BPA.

Another example is the Biosci.Biotech.Biochem.1996,60,683, before the enzymatic resolution step is not performed, the method provided by the articles could not be obtained with a certain L-BPA optical purity; 10 and the method for preparing boronated agents when also relates to multi-step, resulting in conversion of boron-rich material 10 occurs during the manufacturing process. Therefore, the method provided in this document is also not suitable for the synthesis of 10- boron-rich L-BPA.

Furthermore, Bull. Chem. Soc. Jpn. 2000, 73, 231 discloses the use of palladium to catalyze 4-iodo-L-phenylalanine with 4,4,5,5-tetramethyl-1,3,2 A method in which a dioxonium pentoxide (common name: pinacolborane) is subjected to a coupling reaction. However, this document does not mention how to prepare articles 10 boron enriched L-BPA using this method, and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane not a commercial 10 The compounds available in the literature are not suitable for the synthesis of 10- boron-rich L-BPA.

In addition, Synlett. 1996, 167 discloses a method for coupling a iodophenylborate with a zinc derivative of L-serine zinc derivatives, which involves first preparing phenyl iodoborate. The ester and the preparation of a zinc derivative of L-type serine acid, etc., result in a lower yield of the produced L-BPA. In addition, since the 10- boron-rich triiodide 10 boron and 1,3-diphenylpropane-1,3-diol selected for this method are not commercially available compounds, the methods provided in this document are also provided. Still not suitable for the synthesis of 10- boron-rich L-BPA.

SYN

Repub. Korean Kongkae Taeho Kongbo, 2018060319,

PAPER

Research and Development in Neutron Capture Therapy, Proceedings of the International Congress on Neutron Capture Therapy, 10th, Essen, Germany, Sept. 8-13, 2002 (2002), 1-8.

PAPER

European Journal of Pharmaceutical Sciences (2003), 18(2), 155-163

https://www.sciencedirect.com/science/article/abs/pii/S0928098702002567

Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an asymmetric pathway - ScienceDirect
Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an asymmetric pathway - ScienceDirect

PAPER

Tetrahedron Letters (2008), 49(33), 4977-4980

PATENT

WO 2004009135

PATENT

US 20130331599

PATENT

WO 2017028751

https://patents.google.com/patent/WO2017028751A1/en

Example 1

Before preparing (S)-N-tert-butoxycarbonyl-4-dihydroxyborylphenylalanine from (S)-N-tert-butoxycarbonyl-4-iodophenylalanine, it is necessary to reveal Process for preparing (S)-N-tert-butoxycarbonyl-4-iodophenylalanine by using (S)-4-iodophenylalanine as a starting material and a process for preparing 10 tributyl borate with 10 boric acid.

1. Preparation of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine from (S)-4-iodophenylalanine

Please refer to the following reaction formula I, which is (S)-4-iodophenylalanine in a solvent of 1,4-dioxane (1,4-dioxane) and water (H 2 O) with hydrogen peroxide. Sodium (NaOH) and di-tert-butyl dicarbonate (Boc 2 O) are reacted to obtain a chemical reaction formula of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine.

Figure PCTCN2016094881-appb-000005

In the preparation process, two reaction vessels were selected for the reaction.

The specific operation process is as follows:

1. Set up a reaction using a 3L three-neck bottle.

2. (S)-4-iodo-L-phenylalanine (200.00 g, 687.10 mmol, 1.00 eq) was added to the reaction system.

3. Add 1,4-dioxane (1.00 L) and water (1.00 L) to the reaction system, respectively.

4. Sodium hydroxide (68.71 g, 1.72 mol, 2.50 eq) was added to the reaction system, the solution gradually became clear, and the temperature rose slightly to 19 °C.

5. When the system is cooled to 0-10 ° C, di-tert-butyl dicarbonate (254.93 g, 1.17 mol, 268.35 mL, 1.70 eq) is added to the reaction system, and the temperature of the reaction system is naturally raised to 10 to 30 ° C and Stir at room temperature (about 30 ° C) for 8 hours.

6. The reaction was detected using high performance liquid chromatography (HPLC) until the starting of the reaction.

7. The temperature of the control system is less than 40 ° C, and the 1,4-dioxane in the reaction solution is concentrated.

8. The reaction system was lowered to room temperature (about 25 ° C), 100 mL of water was added, and the pH was adjusted to 1.8-2 with hydrochloric acid (2M (ie, molarity, M)).

9. Extract three times with ethyl acetate (2 L).

10. Combine the organic phases and wash twice with saturated brine (1 L).

11. The organic phase was dried over sodium sulfate (200 g).

12. Continue drying in an oven (40-45 ° C) to give (S)-N-tert-butoxycarbonyl-4-iodo-L-phenylalanine (250.00 g, 626.28 mmol, HPLC analysis, yield 93.00 %, purity 98%).

The prepared (S) -N- tert-butoxycarbonyl-4-iodo-phenylalanine was -L- Hydrogen 1 nuclear magnetic resonance spectrum analysis (1 HNMR) as follows:

1 H NMR: (400 MHz DMSO-d 6 )

δ 7.49 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 7.8 Hz, 2H), 5.80 (d, J = 5.9 Hz, 1H), 3.68 (d, J = 5.5 Hz, 1H), 3.00-2.90 (m, 1H), 2.87-2.75 (m, 1H), 1.35-1.15 (m, 9H).

Second, tributyl borate 10 was prepared from boronic acid 10

See the following reaction formulas II, 10 as boric acid (H 2 SO 4) is reacted with sulfuric acid in a solvent (butan-1-ol), and toluene (Toluene) in n-butanol, to obtain 10 tributyl borate (10 The chemical reaction formula of B(OBu) 3 ).

Figure PCTCN2016094881-appb-000006

The specific operation process is as follows:

1. Set up a reaction device R1 using a 3L three-necked bottle, and configure a water separator on the device.

2. 10 boric acid (150.00 g, 2.46 mol, 1.00 eq) was added to the reaction R1 at room temperature (about 25 ° C).

3. Add n-butanol (1.00 L) to the reaction R1 at room temperature (about 25 ° C) and stir, and most of the boric acid cannot be dissolved.

4. Toluene (1.00 L) was added to the reaction R1 at room temperature (about 25 ° C) and stirred.

5. Concentrated sulfuric acid (4.82 g, 49.16 mmol, 2.62 mL, 0.02 eq) was added dropwise to the reaction at room temperature (about 25 ° C), at which time a large amount of solid remained undissolved.

6. The reaction system was heated to 130 ° C, and the water was continuously removed, stirred for 3.5 hours, and water (about 140 g) was formed in the water separator. The solids were all dissolved, and the solution changed from colorless to brown. .

7. TLC (DCM: MeOH = 5:1, Rf = 0.43, bromocresol green).

8. Distill off most of the toluene at atmospheric pressure.

9. After most of the toluene is distilled off, the temperature of the system is lowered to 20 to 30 ° C, and the reaction liquids of the two reactions are combined, and the apparatus is changed for distillation.

10. Oil bath external temperature 108-110 ° C pump distillation under reduced pressure, Kelvin thermometer 45 ° C, distilled n-butanol.

11. Oil bath external temperature 108-110 ° C oil pump distillation under reduced pressure, the residual butanol was distilled off.

12. Oil bath external temperature 118-120 ° C oil pump vacuum distillation, Kelvin thermometer 55 ° C, began to produce products.

13. The temperature is raised to 135-140 ° C oil pump vacuum distillation, the product is completely distilled.

14. The product is obtained as a colorless liquid 10 tributyl borate (830.00g, 3.62mol, yield 73.58%).

The results of the 1 H NMR analysis of the obtained tributyl 10 borate were as follows:

1 H NMR: (400 MHz CDCl 3 )

δ 3.82-3.68 (m, 6H), 1.57-1.42 (m, 6H), 1.34 (qd, J = 7.4, 14.9 Hz, 6H), 0.95-0.80 (m, 9H).

Three, -N- tert-butoxycarbonyl-4-iodo-phenylalanine was prepared (S) of (S) -N- tert-butoxycarbonyl-4-hydroxy-10-yl -L- phenylalanine boron

Please refer to the following reaction formula III, which is (S)-N-tert-butoxycarbonyl-4-iodophenylalanine with tributyl 10 borate, t-butyl magnesium chloride (t-BuMgCl) and bis (2-A) yl aminoethyl) ether (BDMAEE) reaction, to produce (S) -N- tert-butoxycarbonyl group -4- (10 B) dihydroxyboryl -L- phenylalanine chemical reaction.

Figure PCTCN2016094881-appb-000007

In the preparation process, two reaction vessels were selected for the reaction.

The specific operation process is as follows:

1. Set up a reaction using a 3L three-neck bottle.

2. Tributyl 10 borate (187.60 g, 87.98 mmol, 3.20 eq) was placed in the reaction system at room temperature (about 22 ° C).

3. Sodium hydride (20.45 g, 511.24 mmol, purity 60%, 2.00 eq) was added to the reaction system at room temperature (about 22 ° C). The reaction solution was a suspension and stirred at room temperature (about 22 ° C). 5 minutes.

4. Bis(2-methylaminoethyl)ether (327.73 g, 2.04 mol, 8.00 eq) was added to the reaction at room temperature (about 22 ° C).

5. N-tert-Butoxycarbonyl-4-iodo-L-phenylalanine (100.00 g, 255.62 mmol, 1.00 eq) was added to the reaction system at room temperature (about 22 ° C), and a large amount of solid was not dissolved.

6. Lower the temperature of the reaction system to 0-5 ° C, add t-butyl magnesium chloride (1.7 M, 1.20 L, 2.04 mol, 8.00 eq) to the reaction, control the temperature between 0-10 ° C, the dropping time is about It is 1.5 hours.

7. After the completion of the charging, the temperature of the reaction system was naturally raised to room temperature (20 to 30 ° C) and stirred at this temperature for 12 hours.

8. Using high performance liquid chromatography (HPLC) to detect about 9.00% of the remaining material.

9. When the temperature of the reaction system was lowered to -5 to 0 ° C, it was quenched by dropwise addition of 500 mL of water.

10. Lower the temperature of the system to 0-5 ° C, add methyl tert-butyl ether (500 mL) to the reaction system and adjust the pH to 2.9-3.1 (using a pH meter) with 37% HCl (about 500 mL). Exothermic, the temperature of the control system is between 0-15 °C.

11. The aqueous phase obtained by liquid separation was extracted once with methyl tert-butyl ether (500 mL), and the obtained organic phases were combined to give an organic phase of about 1.1 L.

12. Slowly add a sodium hydroxide aqueous solution (1 M, 400 mL) to the obtained organic phase, exotherm during the dropwise addition, and control the system temperature between 0-15 °C.

13. After the completion of the dropwise addition, the pH of the system was about 10, and the pH was adjusted to between 12.10 and 12.6 with an aqueous sodium hydroxide solution (4M). (measured with a pH meter)

14. Dispensing.

15. The aqueous phase 1 obtained after liquid separation was extracted once with n-butanol (500 ml) to obtain aqueous phase 2.

16. Combine the aqueous phase 2 of the two reaction vessels.

17. Adjust the pH of the aqueous phase to 2.9-3.1 with 37% HCl, stir for about 40 minutes, and precipitate a large amount of solid.

18. Filtration gave a white solid which was washed once with dichloromethane (50 mL).

19. At 25 ° C, the precipitated solid was slurried with dichloromethane (150 mL) and stirred for 10 min.

20. A white solid was filtered to give (S) -N- tert-butoxycarbonyl group -4- (10 B) dihydroxyboryl -L- phenylalanine (75.00g, 240.82mmol, by HPLC analysis, a yield of 47.11% , purity 99%).

The prepared (S) -N- tert-butoxycarbonyl group -4- (10 B) results dihydroxyboryl -L- phenylalanine 1 HNMR was as follows:

1 H NMR: (400 MHz DMSO-d 6 )

Δ12.55 (br.s., 1H), 7.91 (s, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 7.5 Hz, 2H), 4.08-4.01 (m, 1H) ), 3.61-3.53 (m, 1H), 2.98 (dd, J = 4.2, 13.9 Hz, 1H), 2.79 (dd, J = 10.4, 13.5 Hz, 1H), 1.79-1.67 (m, 1H), 1.35- 1.17 (m, 9H).

Preparation of L- 10 BPA from (S)-N-tert-Butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine

See the following reaction scheme IV, which is (S) -N- tert-butoxycarbonyl group -4- (10 B) of amine end dihydroxyboryl -L- phenylalanine deprotection of the chemical reaction, to obtain L- 10 BPA.

Figure PCTCN2016094881-appb-000008

The specific operation process is as follows:

1. Set up a reaction using a 1L three-neck bottle.

2. room temperature (20-30 deg.] C) to (S) -N- tert-butoxycarbonyl group -4- (10 B) dihydroxyboryl -L- phenylalanine (67.00g, 217.31mmol, 1.00eq) was added the reaction In the system.

3. room temperature (20-30 deg.] C) water (23.75mL) and acetone (Acetone, 420.00mL) were added dropwise to the reaction flask, stirred (S) -N- tert-butoxycarbonyl group -4- (10 B) dihydroxy Boronyl-L-phenylalanine.

4. Concentrated hydrochloric acid (23.93 g, 656.28 mmol, 23.46 mL, 3.02 eq) was added dropwise to the reaction system at room temperature (20-30 ° C). After the addition was completed, the reaction system was heated to 55-60 ° C and stirred for 4.5 hours.

5. HPLC detection until the reaction of the starting material is completed.

6. The temperature is controlled below 40 ° C, and the acetone in the reaction system is concentrated.

7. Lower the concentrated system to below 15 °C, adjust the pH of the system to about 1.5 with sodium hydroxide solution (4M) (pH meter detection), stir for 40 minutes and continue to adjust the pH of the system to 6.15 using sodium hydroxide solution (4M). ~6.25, a large amount of white solid precipitated, which was filtered to give a white solid, and rinsed with acetone (200mL).

8. Obtained as a white solid L- 10 BPA (36.00 g, 171.17 mmol, HPLC, yield 78.77%, purity 99%).

The analytical results obtained by the L- 10 BPA 1 HNMR are as follows:

1 H NMR: (400 MHz D 2 O, CF 3 COOH)

δ 7.44 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 4.06 (dd, J = 5.7, 7.5 Hz, 1H), 3.11-3.01 (m, 1H), 2.98 -2.87 (m, 1H).

xample 6

Preparation of (S)-N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine from (S)-N-tert-butoxycarbonyl-4-iodophenylalanine

Please refer to the following reaction formula VII, which is a reaction of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine with tributyl borate and t-butylmagnesium chloride (t-BuMgCl) to obtain (S The chemical reaction formula of -N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine.

Figure PCTCN2016094881-appb-000013

The specific operation process is as follows:

1. Construct a reaction unit with a 250 mL three-neck bottle.

2. Tributyl borate (17.65 g, 76.68 mmol, 3.00 eq) was placed in a 250 mL reaction flask at 20-30 °C.

3. Sodium hydride (1.02 g, 25.56 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

4. (S)-N-tert-Butoxycarbonyl-4-iodo-L-phenylalanine (10.00 g, 25.56 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

5. Reduce the temperature of the reaction system to 0 ° C under nitrogen atmosphere, slowly add t-butyl magnesium chloride (1.7 M in THF, 120 mL, 8.00 eq) to the reaction, the dropping time is about 30 minutes, and the control temperature is 0. Between °C and 10 °C.

Stir at 20.20 ~ 30 ° C for 20 hours.

7. HPLC detection of the basic reaction of the raw materials, leaving only about 0.7% of the raw materials.

8. At a temperature of 0 ° C, 5 mL of water was added dropwise to the reaction to quench it. After complete quenching, stirring was continued for 10 minutes.

9. Cool down to 0 ° C, add methyl tert-butyl ether (50 mL) to the reaction and adjust the pH to 3 with 37% HCl (about 50 mL) (detected with a pH meter), adjust the pH during the process to exotherm, control the temperature at 0 Between °C and 15 °C.

12. The aqueous phase obtained by liquid separation was extracted once with methyl t-butyl ether (50 mL) and the organic phases were combined.

12. Add NaOH solution (1M, 55mL) to the obtained organic phase to adjust the pH to between 12.10-12.6. The process is exothermic and the temperature is controlled between 0 °C and 15 °C.

13. Liquid separation, the obtained aqueous phase was extracted once with n-butanol (50 mL), and most of the impurities were extracted and removed.

14. The aqueous phase obtained by liquid separation was adjusted to pH 3 with 37% HCl and stirred for about 30 minutes to precipitate a white solid.

15. Filtration gave a white solid which was washed once with dichloromethane (50 mL).

16. The precipitated solid was slurried with 25 mL of dichloromethane at 25 ° C and stirred for 10 minutes.

17. Filtration of (S)-N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine (6.8 g, HPLC, yield: 83.15%, purity 98%).

Example 7

Please continue to refer to Reaction Scheme VII. The specific operation process is as follows:

1. Construct a reaction unit with a 250 mL three-neck bottle.

2. Tributyl borate (8.82 g, 38.34 mmol, 3.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

3. Sodium hydride (511.25 mg, 12.78 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

4. (S)-N-tert-Butoxycarbonyl-4-iodo-L-phenylalanine (5.00 g, 12.78 mmol, 1.00 eq) was added to a 250 mL reaction vial at 20-30 °C.

5. The temperature of the reaction system was lowered to 0 ° C under nitrogen atmosphere, and t-butyl magnesium chloride (1.7 M in THF, 60 mL, 8.00 eq) was added dropwise to the reaction, the dropwise addition time was about 30 minutes, and the control temperature was 0 ° C. -10 ° C between.

Stir at 6.20 ~ 30 ° C for 22 hours.

7. HPLC detection of the raw material reaction is completed.

8. At a temperature of 0 ° C, 2.5 mL of water was added dropwise to the reaction to quench it. After complete quenching, stirring was continued for 10 minutes.

9. Cool down to 0 ° C, add methyl tert-butyl ether (25 mL) to the reaction and adjust the pH to 3 with 37% HCl (about 25 mL) (detected with a pH meter), adjust the pH during the process to exotherm, control the temperature at 0 Between °C and 15 °C.

12. The aqueous phase obtained by liquid separation was extracted once with methyl t-butyl ether (25 mL) and the organic phases were combined.

12. Add NaOH solution (1M, 30mL) to the obtained organic phase to adjust the pH to between 12.10-12.6. The process is exothermic and the temperature is controlled between 0 °C and 15 °C.

13. Liquid separation, the obtained aqueous phase was extracted once with n-butanol (25 ml), and most of the impurities were extracted and removed.

14. The aqueous phase obtained by liquid separation was adjusted to pH 3 with 37% HCl and stirred for about 30 minutes to precipitate a white solid.

15. Filtration gave a white solid which was washed once with dichloromethane (25 mL).

16. The precipitated solid was slurried with 15 mL of dichloromethane at 25 ° C and stirred for 10 minutes.

17. Filtration gave (S)-N-tert-butoxycarbonyl-4-dihydroxyboryl-L-phenylalanine (3.4 g, obtained by HPLC, yield: 85.26%, purity 98%).

Bis(2-methylaminoethyl)ether is a complexing agent for Mg, which can reduce the occurrence of side reactions in the reaction. The reactions of Examples 6 and 7 were carried out without adding bis(2-methylaminoethyl)ether. The analysis showed that the iodine impurity in the reaction of Example 6 was about 17%, and the iodine impurity in the reaction of Example 7 was observed. About 28%. Therefore, it has been proved from the side that the addition of bis(2-methylaminoethyl)ether can protect the reaction from reducing iodine.

The BPA or 10 BPA obtained in the above examples were analyzed by chiral HPLC, and the ratio of the L-enantiomer to the D-enantiomer was 100:0.

The boron-containing drug L-BPA for neutron capture therapy disclosed in the present invention is not limited to the contents described in the above examples. The above-mentioned embodiments are only examples for convenience of description, and the scope of the claims should be determined by the claims.

PATENT

KR 2018060319

PATENT

WO 2019163790

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019163790

///////////Borofalan (10B), Borofalan, Steboronine, JAPAN 2020, 2020 APPROVALS, ボロファラン (10B), ボロファラン , 硼[10B]法仑 , 

B(C1=CC=C(C=C1)CC(C(=O)O)N)(O)O

Copper Cu 64 dotatate, 銅(Cu64)ドータテート;


Copper dotatate Cu-64.png

2D chemical structure of 1426155-87-4

Figure imgf000004_0001

Copper Cu 64 dotatate

銅(Cu64)ドータテート;

UNII-N3858377KC

N3858377KC

Copper 64-DOTA-tate

Copper Cu-64 dotatate

Copper dotatate Cu-64

Diagnostic (neuroendocrine tumors), Radioactive agent

Formula
C65H86CuN14O19S2. 2H
CAS:
 1426155-87-4
Mol weight
1497.1526

FDA APPROVED 2020. 2020/9/3. Detectnet

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-10-(carboxylatomethyl)-7-(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;copper-64(2+)

Cuprate(2-)-64Cu, (N-(2-(4,10-bis((carboxy-kappaO)methyl)-7-(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl-kappaN1,kappaN4,kappaN7,kappaN10)acetyl)-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoni

Copper Cu 64 dotatate, sold under the brand name Detectnet, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adults.[1]

Common side effects include nausea, vomiting and flushing.[2]

It was approved for medical use in the United States in September 2020.[1][2]

History

The U.S. Food and Drug Administration (FDA) approved copper Cu 64 dotatate based on data from two trials that evaluated 175 adults.[3]

Trial 1 evaluated adults, some of whom had known or suspected NETs and some of whom were healthy volunteers.[3] The trial was conducted at one site in the United States (Houston, TX).[3] Both groups received copper Cu 64 dotatate and underwent PET scan imaging.[3] Trial 2 data came from the literature-reported trial of 112 adults, all of whom had history of NETs and underwent PET scan imaging with copper Cu 64 dotatate.[3] The trial was conducted at one site in Denmark.[3] In both trials, copper Cu 64 dotatate images were compared to either biopsy results or other images taken by different techniques to detect the sites of a tumor.[3] The images were read as either positive or negative for presence of NETs by three independent image readers who did not know participant clinical information.[3]

PATENT

https://patents.google.com/patent/WO2013029616A1/en

PATENT

https://patents.google.com/patent/US20140341807

  • Known imaging techniques with tremendous importance in medical diagnostics are positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), single photon computed tomography (SPECT) and ultrasound (US). Although today’s imaging technologies are well developed they rely mostly on non-specific, macroscopic, physical, physiological, or metabolic changes that differentiate pathological from normal tissue.
  • [0003]
    Targeting molecular imaging (MI) has the potential to reach a new dimension in medical diagnostics. The term “targeting” is related to the selective and highly specific binding of a natural or synthetic ligand (binder) to a molecule of interest (molecular target) in vitro or in vivo.
  • [0004]
    MI is a rapidly emerging biomedical research discipline that may be defined as the visual representation, characterization and quantification of biological processes at the cellular and sub-cellular levels within intact living organisms. It is a novel multidisciplinary field, in which the images produced reflect cellular and molecular pathways and in vivo mechanism of disease present within the context of physiologically authentic environments rather than identify molecular events responsible for disease.
  • [0005]
    Several different contrast-enhancing agents are known today and their unspecific or non-targeting forms are already in clinical routine. Some examples listed below are reported in literature.
  • [0006]
    For example, Gd-complexes could be used as contrast agents for MRI according to “Contrast Agents I” by W. Krause (Springer Verlag 2002, page one and following pages). Furthermore, superparamagnetic particles are another example of contrast-enhancing units, which could also be used as contrast agents for MRI (Textbook of Contrast Media, Superparamagnetic Oxides, Dawson, Cosgrove and Grainger Isis Medical Media Ltd, 1999, page 373 and following pages). As described in Contrast Agent II by W. Krause (Springer Verlag 2002, page 73 and following pages), gas-filled microbubbles could be used in a similar way as contrast agents for ultrasound. Moreover “Contrast Agents II” by W. Krause (Springer Verlag, 2002, page 151 and following pages) reports the use of iodinated liposomes or fatty acids as contrast agents for X-Ray imaging.
  • [0007]
    Contrast-enhancing agents that can be used in functional imaging are mainly developed for PET and SPECT.
  • [0008]
    The application of radiolabelled bioactive peptides for diagnostic imaging is gaining importance in nuclear medicine. Biologically active molecules which selectively interact with specific cell types are useful for the delivery of radioactivity to target tissues. For example, radiolabelled peptides have significant potential for the delivery of radionuclides to tumours, infarcts, and infected tissues for diagnostic imaging and radiotherapy.
  • [0009]
    DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10tetraazacyclododecane) and its derivatives constitute an important class of chelators for biomedical applications as they accommodate very stably a variety of di- and trivalent metal ions. An emerging area is the use of chelator conjugated bioactive peptides for labeling with radiometals in different fields of diagnostic and therapeutic nuclear oncology.
  • [0010]
    There have been several reports in recent years on targeted radiotherapy with radiolabeled somatostatin analogs.
  • [0011]
    US2007/0025910A1 discloses radiolabled somatostatin analogs primarily based on the ligand DOTA-TOC. The radionucleotide can be (64)Copper and the somatostatin analog may be octreotide, lanreotide, depreotide, vapreotide or derivatives thereof. The compounds of US2007/0025910A1 are useful in radionucleotide therapy of tumours.
  • [0012]
    US2007/0025910A1 does not disclose (64)Cu-DOTA-TATE. DOTA-TATE and DOTA-TOC differ clearly in affinity for the 5 known somatostatin receptors (SST1-SST2). Accordingly, the DOTA-TATE has a 10-fold higher affinity for the SST2 receptor, the receptor expressed to the highest degree on neuroendocrine tumors. Also the relative affinity for the other receptor subtypes are different. Furthermore, since 177Lu-DOTATATE is used for radionuclide therapy, only 64Cu-DOTATATE and not 64Cu-DOTATOC can be used to predict effect of such treatment by a prior PET scan.
  • [0013]
    There exists a need for further peptide-based compounds having utility for diagnostic imaging techniques, such as PET.

Figure US20140341807A1-20141120-C00001

    • EXAMPLE
  • [0033]
    Preparation of “Cu-Dotatate-DOTA-TATE
  • [0034]
    64Cu was produced using a GE PETtrace cyclotron equipped with a beamline. The 64Cu was produced via the 64Ni (p,n) 64Cu reaction using a solid target system consisting of a water cooled target mounted on the beamline. The target consisted of 64Ni metal (enriched to >99%) electroplated on a silver disc backing. For this specific type of production a proton beam with the energy of 16 MeV and a beam current of 20 uA was used. After irradiation the target was transferred to the laboratory for further chemical processing in which the 64Cu was isolated using ion exchange chromatography. Final evaporation from aq. HCl yielded 2-6 GBq of 64Cu as 64CuCl2 (specific activity 300-3000 TBq/mmol; RNP >99%). The labeling of 64Cu to DOTA-TATE was performed by adding a sterile solution of DOTA-TATE (0.3 mg) and Gentisic acid (25 mg) in aq Sodium acetate (1 ml; 0.4M, pH 5.0) to a dry vial containing 64CuCl2 (˜1 GBq). Gentisic acid was added as a scavenger to reduce the effect of radiolysis. The mixture was left at ambient temperature for 10 minutes and then diluted with sterile water (1 ml). Finally, the mixture was passed through a 0.22 μm sterile filter (Millex GP, Millipore). Radiochemical purity was determined by RP-HPLC and the amount of unlabeled 64Cu2+ was determined by thin-layer chromatography. All chemicals were purchased from Sigma-Aldrich unless specified otherwise. DOTA-Tyr3-Octreotate (DOTA-TATE) was purchased from Bachem (Torrance, Calif.). Nickel-64 was purchased in +99% purity from Campro Scientific Gmbh. All solutions were made using Ultra pure water (<0.07 μSimens/cm). Reversed-phase high pressure liquid chromatography was performed on a Waters Alliance 2795 Separations module equipped with at Waters 2489 UV/Visible detector and a Caroll Ramsey model 105 S-1 radioactivity detector—RP-HPLC column was Luna C18, HST, 50×2 mm, 2.5 μm, Phenomenex. The mobile phase was 5% aq. acetonitrile (0.1% TFA) and 95% aq. acetonitrile (0.1% TFA).
  • [0035]
    Thin layer chromatography was performed with a Raytest MiniGita Star TLC-scanner equipped with a Beta-detector. The eluent was 50% aq methanol and the TLC-plate was a Silica60 on Al foil (Fluka). Ion exchange chromatography was performed on a Dowex 1×8 resin (Chloride-form, 200-400 mesh).

References

  1. Jump up to:a b “FDA approval letter” (PDF). 3 September 2020. Retrieved 5 September 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b “RadioMedix and Curium Announce FDA Approval of Detectnet (copper Cu 64 dotatate injection) in the U.S.” (Press release). Curium. 8 September 2020. Retrieved 9 September 2020 – via GlobeNewswire.
  3. Jump up to:a b c d e f g h “Drug Trials Snapshots: Detectnet”U.S. Food and Drug Administration (FDA). 3 September 2020. Retrieved 10 September 2020.  This article incorporates text from this source, which is in the public domain.

External links

Coppers Coming | Cu 64 dotatate injection is coming soonThe emerging role of copper-64 radiopharmaceuticals as cancer theranostics  - ScienceDirect

The emerging role of copper-64 radiopharmaceuticals as cancer theranostics  - ScienceDirect

The FDA has approved copper Cu 64 dotatate injection (Detectnet) for the localization of somatostatin receptor–positive neuroendocrine tumors (NETs), according to an announcement from RadioMedix Inc. and Curium Pharma.1

The positron emission tomography (PET) diagnostic agent is anticipated to launch immediately, according to Curium. Doses will be accessible through several nuclear pharmacies or through the nuclear medicine company.

“Detectnet brings an exciting advancement in the diagnosis of NETs for healthcare providers, patients, and their caregivers,” Ebrahim Delpassand MD, CEO of RadioMedix, stated in a press release. “The phase 3 results demonstrate the clinical sensitivity and specificity of Detectnet which will provide a great aid to clinicians in developing an accurate treatment approach for their [patients with] NETs.”

Copper Cu 64 dotatate adheres to somatostatin receptors with highest affinity for subtype 2 receptors (SSTR2). Specifically, the agent binds to somatostatin receptor–expressing cells, including malignant neuroendocrine cells; these cells overexpress SSTR2. The agent is a positron-producing radionuclide that possesses an emission yield that permits PET imaging.

“Perhaps most exciting is that the 12.7-hour half-life allows Detectnet to be produced centrally and shipped to sites throughout the United States,” added Delpassand. “This will help alleviate shortages or delays that have been experienced with other somatostatin analogue PET agents.”

Two single-center, open-label studies confirmed the efficacy of the diagnostic agent, according to Curium.2 In Study 1, investigators conducted a prospective analysis of 63 patients, which included 42 patients with known or suspected NETs according to histology, conventional imaging, or clinical evaluations, and 21 healthy volunteers. The majority of the participants, or 88% (n = 37) had a history of NETs at the time that they underwent imaging. Just under half of patients (44%; n = 28) were men and the majority were white (86%). Moreover, patients had a mean age of 54 years.

Images produced by the PET agent were interpreted to be either positive or negative for NET via 3 independent readers who had been blinded to the clinical data and other imaging information. Moreover, the results from the diagnostic agent were compared with a composite reference standard that was comprised of 1 oncologist’s blinded evaluation of patient diagnosis based on available histopathology results, reports of conventional imaging that had been done within 8 weeks before the PET imaging, as well as clinical and laboratory findings, which involved chromogranin A and serotonin levels.

Additionally, the percentage of patients who tested positive for disease via composite reference as well as through PET imaging was used to quantify positive percent agreement. Conversely, the percentage of participants who did not have disease per composite reference and who were determined to be negative for disease per PET imaging was used to quantify negative percent agreement.

Results showed that the percent reader agreement for positive detection in 62 scans was 91% (95% CI, 75-98) and negative detection was 97% (95% CI, 80-99). For reader 2, these percentages were 91% (95% CI, 75-98) and 80% (95% CI, 61-92), respectively, for 63 scans. Lastly, the percent reader agreement for reader 3 in 63 scans was 91% (95% CI, 75-98) positive and 90% (95% CI, 72-97) negative.

Study 2 was a retrospective analysis in which investigators examined published findings collected from 112 patients; 63 patients were male, while 43 were female. The mean age of patients included in the analysis was 62 years. All patients had a known history of NETs. Results demonstrated similar performance with the PET imaging agent.

In both safety and efficacy trials, a total of 71 patients were given a single dose of the diagnostic agent; the majority of these patients had known or suspected NETs and 21 were healthy volunteers. Adverse reactions such as nausea, vomiting, and flushing were reported at a rate of less than 2%. In all clinical experience that has been published, a total of 126 patients with a known history of NETs were given a single dose of the PET diagnostic agent. A total of 4 patients experienced nausea immediately after administration.

“Curium is excited to bring the first commercially available Cu 64 diagnostic agent to the US market,” Dan Brague, CEO of Curium, North America, added in the release. “Our unique production capabilities and distribution network allow us to deliver to any nuclear pharmacy, hospital, or imaging center its full dosing requirements first thing in the morning, to provide scheduling flexibility to the institution and its patients. We look forward to joining with healthcare providers and our nuclear pharmacy partners to bring this highly efficacious agent to the market.”

References
1. RadioMedix and Curium announce FDA approval of Detectnet (copper Cu 64 dotatate injection) in the US. News release. RadioMedix Inc and Curium. September 8, 2020. Accessed September 9, 2020. https://bit.ly/3m6iC0q.
2. Detectnet. Prescribing information. Curium Pharma; 2020. Accessed September 9, 2020. https://bit.ly/32eZxS3.

///////////////Copper Cu 64 dotatate, 銅(Cu64)ドータテート , FDA 2020, 2020 APPROVALS, Diagnostic, neuroendocrine tumors, Radioactive agent,

CC(C1C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=C(C=C4)O)NC(=O)C(CC5=CC=CC=C5)NC(=O)CN6CCN(CCN(CCN(CC6)CC(=O)[O-])CC(=O)[O-])CC(=O)O)C(=O)NC(C(C)O)C(=O)O)O.[Cu+2]

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