NeoBOMB1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: NeoBOMB1
• 英文别名: 2-[4-[2-[[4-[[2-[2-[[(2R)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-(2,6-dimethylheptan-4-ylamino)-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethoxy]acetyl]amino]phenyl]methylamino]-2-oxoethyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid
• 化学式: C₇₇H₁₁₀N₁₈O₁₈
• 分子量: 1575.83
• InChiKey: LDDCOMQLHFUMLP-IGEKPEAISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.5
• 重原子数：
  113
• 可旋转键数：
  44
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  513
• 氢给体数：
  16
• 氢受体数：
  23

反应信息

• 作为反应物：
  描述：

  gallium(III) trichloride 、 NeoBOMB1 以 aq. acetate buffer 为溶剂， 反应 0.25h， 以38%的产率得到Ga-NeoBOMB1
  参考文献：
  名称：

  [EN] RADIOLABELED BOMBESIN-DERIVED COMPOUNDS FOR IN VIVO IMAGING OF GASTRIN-RELEASING PEPTIDE RECEPTOR (GRPR) AND TREATMENT OF GRPR-RELATED DISORDERS
  [FR] COMPOSÉS RADIOMARQUÉS DÉRIVÉS DE LA BOMBÉSINE POUR L'IMAGERIE IN VIVO DU RÉCEPTEUR DU PEPTIDE LIBÉRANT DE LA GASTRINE (GRPR) ET TRAITEMENT DES TROUBLES LIÉS AU GRPR

  摘要：

  提供了Formula Ia（RX-L-Xaa1-Gln-Trp-Ala-Val-Xaa2-His-Xaa3-ψ-Xaa4-NH2）的波美斯因衍生物。RX包括放射性同位素螯合剂或三氟硼酸酯含基团。L是连接剂。Xaa1是D-Phe，Cpa（4-氯苯丙氨酸），D-Cpa，Tpi（2,3,4,9-四氢-1H-吡啶[3,4b]吲哚-3-羧酸），D-Tpi，Nal（萘丙氨酸）或D-Nal。Xaa2是Gly，N-甲基-Gly或D-Ala。Xaa3是Leu，Pro，D-Pro或Phe。Xaa4是Pro，Phe，Tac（噻唑啉-4-羧酸），Nle（正癸氨酸），4-氧代-L-Pro（噁唑啉-4-羧酸）。符号ψ代表Xaa3和Xaa4之间的还原肽键，其中当Xaa4为Pro，Tac或4-氧代-L-Pro时，ψ为CH2-N，或当Xaa4为Phe或Nle时，ψ为CH2N(R)，其中R为H或C1-C5线性或支链烷基。还提供了将这些化合物用作成像剂或治疗剂的用途。

  公开号：

  WO2021068051A1
• 作为产物：
  描述：

  Fmoc-Rink resin 、 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸 、 1-异丁基-3-甲基丁胺 、 Fmoc-甘氨酸 、 Fmoc-L-缬氨酸 、 Fmoc-L-丙氨酸 、 Fmoc-p-aminomethylaniline-diglycolic acid 、 Fmoc-N-三苯甲基-L-谷氨酰胺 、 Fmoc-D-苯丙氨酸 、 N-Fmoc-N'-三苯甲基-L-组氨酸 、 Fmoc-L-色氨酸(Boc)-OH 在 溶剂黄146 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以39%的产率得到NeoBOMB1
  参考文献：
  名称：

  [EN] RADIOLABELED BOMBESIN-DERIVED COMPOUNDS FOR IN VIVO IMAGING OF GASTRIN-RELEASING PEPTIDE RECEPTOR (GRPR) AND TREATMENT OF GRPR-RELATED DISORDERS
  [FR] COMPOSÉS RADIOMARQUÉS DÉRIVÉS DE LA BOMBÉSINE POUR L'IMAGERIE IN VIVO DU RÉCEPTEUR DU PEPTIDE LIBÉRANT DE LA GASTRINE (GRPR) ET TRAITEMENT DES TROUBLES LIÉS AU GRPR

  摘要：

  提供了Formula Ia（RX-L-Xaa1-Gln-Trp-Ala-Val-Xaa2-His-Xaa3-ψ-Xaa4-NH2）的波美斯因衍生物。RX包括放射性同位素螯合剂或三氟硼酸酯含基团。L是连接剂。Xaa1是D-Phe，Cpa（4-氯苯丙氨酸），D-Cpa，Tpi（2,3,4,9-四氢-1H-吡啶[3,4b]吲哚-3-羧酸），D-Tpi，Nal（萘丙氨酸）或D-Nal。Xaa2是Gly，N-甲基-Gly或D-Ala。Xaa3是Leu，Pro，D-Pro或Phe。Xaa4是Pro，Phe，Tac（噻唑啉-4-羧酸），Nle（正癸氨酸），4-氧代-L-Pro（噁唑啉-4-羧酸）。符号ψ代表Xaa3和Xaa4之间的还原肽键，其中当Xaa4为Pro，Tac或4-氧代-L-Pro时，ψ为CH2-N，或当Xaa4为Phe或Nle时，ψ为CH2N(R)，其中R为H或C1-C5线性或支链烷基。还提供了将这些化合物用作成像剂或治疗剂的用途。

  公开号：

  WO2021068051A1

文献信息

• NeoBOMB1, a GRPR-Antagonist for Breast Cancer Theragnostics: First Results of a Preclinical Study with [67Ga]NeoBOMB1 in T-47D Cells and Tumor-Bearing Mice
  作者：Aikaterini Kaloudi、Emmanouil Lymperis、Athina Giarika、Simone Dalm、Francesca Orlandi、Donato Barbato、Mattia Tedesco、Theodosia Maina、Marion de Jong、Berthold Nock

  DOI：10.3390/molecules22111950

  日期：——

  Background: The GRPR-antagonist-based radioligands [67/68Ga/111In/177Lu]NeoBOMB1 have shown excellent theragnostic profiles in preclinical prostate cancer models, while [68Ga]NeoBOMB1 effectively visualized prostate cancer lesions in patients. We were further interested to explore the theragnostic potential of NeoBOMB1 in GRPR-positive mammary carcinoma, by first studying [67Ga]NeoBOMB1 in breast cancer models; Methods: We investigated the profile of [67Ga]NeoBOMB1, a [68Ga]NeoBOMB1 surrogate, in GRPR-expressing T-47D cells and animal models; Results: NeoBOMB1 (IC50s of 2.2 ± 0.2 nM) and [natGa]NeoBOMB1 (IC50s of 2.5 ± 0.2 nM) exhibited high affinity for the GRPR. At 37 °C [67Ga]NeoBOMB1 strongly bound to the T-47D cell-membrane (45.8 ± 0.4% at 2 h), internalizing poorly, as was expected for a radioantagonist. [67Ga]NeoBOMB1 was detected >90% intact in peripheral mouse blood at 30 min pi. In mice bearing T-47D xenografts, [67Ga]NeoBOMB1 specifically localized in the tumor (8.68 ± 2.9% ID/g vs. 0.6 ± 0.1% ID/g during GRPR-blockade at 4 h pi). The unfavorably high pancreatic uptake could be considerably reduced (206.29 ± 17.35% ID/g to 42.46 ± 1.31% ID/g at 4 h pi) by increasing the NeoBOMB1 dose from 10 pmol to 200 pmol, whereas tumor uptake remained unaffected. Notably, tumor values did not decline from 1 to 24 h pi; Conclusions: [67Ga]NeoBOMB1 can successfully target GRPR-positive breast cancer in animals with excellent prospects for clinical translation.

  背景：基于GRPR拮抗剂的放射性配体[67/68Ga/111In/177Lu]NeoBOMB1在临床前前列腺癌模型中显示出了极佳的疗效，而[68Ga]NeoBOMB1则能有效显示患者的前列腺癌病灶。通过首先研究乳腺癌模型中的[67Ga]NeoBOMB1，我们进一步探索了 NeoBOMB1 在 GRPR 阳性乳腺癌中的治疗潜力：我们研究了[67Ga]NeoBOMB1（一种[68Ga]NeoBOMB1替代物）在表达GRPR的T-47D细胞和动物模型中的概况；结果：[67Ga]NeoBOMB1（IC50）在GRPR阳性乳腺癌中的预后潜力为0.5%：NeoBOMB1（IC50 为 2.2 ± 0.2 nM）和[natGa]NeoBOMB1（IC50 为 2.5 ± 0.2 nM）对 GRPR 具有高亲和力。37 °C时，[67Ga]NeoBOMB1与T-47D细胞膜结合力很强（2小时内为45.8 ± 0.4%），内化程度很低，这也是放射性拮抗剂的预期效果。30 分钟后，在小鼠外周血中检测到的[67Ga]NeoBOMB1 的完整率大于 90%。在T-47D异种移植小鼠体内，[67Ga]NeoBOMB1特异性地定位在肿瘤中（8.68 ± 2.9% ID/g vs. 4 h pi时GRPR阻断期间的0.6 ± 0.1% ID/g）。通过将 NeoBOMB1 的剂量从 10 pmol 增加到 200 pmol，胰腺摄取的不利的高摄取量可大大减少（4 h pi 时为 206.29 ± 17.35% ID/g 到 42.46 ± 1.31% ID/g），而肿瘤摄取量则不受影响。值得注意的是，肿瘤摄取值在 1 到 24 小时内没有下降：[67Ga]NeoBOMB1能成功地在动物体内靶向GRPR阳性乳腺癌，具有良好的临床应用前景。
• Comparison of biological properties of [¹⁷⁷Lu]Lu-ProBOMB1 and [¹⁷⁷Lu]Lu-NeoBOMB1 for GRPR targeting
  作者：Etienne Rousseau、Joseph Lau、Zhengxing Zhang、Chengcheng Zhang、Daniel Kwon、Carlos F. Uribe、Hsiou-Ting Kuo、Jutta Zeisler、Ivica Bratanovic、Kuo-Shyan Lin、François Bénard

  DOI：10.1002/jlcr.3815

  日期：2020.2

  The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer and other solid malignancies. Following up on our work on [68Ga]Ga-ProBOMB1 that had better imaging characteristics than [68Ga]Ga-NeoBOMB1, we investigated the effects of substituting 68Ga for 177Lu to determine if the resulting radiopharmaceuticals could be used with a therapeutic aim. We radiolabeled the bombesin antagonist ProBOMB1 (DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Pro-NH2) with lutetium-177 and compared it with [177Lu]Lu-NeoBOMB1 (obtained in 54.2 ± 16.5% isolated radiochemical yield with >96% radiochemical purity and 440.8 ± 165.1 GBq/μmol molar activity) for GRPR targeting. Lu-NeoBOMB1 had better binding affinity for GRPR than Lu-ProBOMB1 (Ki values: 2.26 ± 0.24 and 30.2 ± 3.23nM). [177Lu]Lu-ProBOMB1 was obtained in 53.7 ± 5.4% decay-corrected radiochemical yield with 444.2 ± 193.2 GBq/μmol molar activity and >95% radiochemical purity. In PC-3 prostate cancer xenograft mice, tumor uptake of [177Lu]Lu-ProBOMB1 was 3.38 ± 1.00, 1.32 ± 0.24, and 0.31 ± 0.04%ID/g at 1, 4, and 24 hours pi. However, the uptake in tumor was lower than [177Lu]Lu-NeoBOMB1 at all time points. [177Lu]Lu-ProBOMB1 was inferior to [177Lu]Lu-NeoBOMB1, which had better therapeutic index for the organs receiving the highest doses.

  NeoB鄒BOMB1在PC-3前列腺癌异种移植小鼠体内的肿瘤摄取率在注射后1、4和24小时分别为3.38 ± 1.00、1.32 ± 0.24和0.31 ± 00.04%ID/g。然而，在所有时间点，肿瘤的摄取率均低于[177Lu]Lu-NeoBOMB1。
• GRPR-ANTAGONISTS FOR DETECTION, DIAGNOSIS AND TREATMENT OF GRPR-POSITIVE CANCER
  申请人：Advanced Accelerator Applications USA, Inc.

  公开号：EP3536347A1

  公开（公告）日：2019-09-11

  The present invention relates to probes for use in the detection, imaging, diagnosis, targeting, treatment, etc. of cancers expressing the gastrin releasing peptide receptor (GRPR). For example, such probes may be molecules conjugated to detectable labels which are preferably moieties suitable for detection by gamma imaging and SPECT or by positron emission tomography (PET) or magnetic resonance imaging (MRI) or fluorescence spectroscopy or optical imaging methods.

  本发明涉及用于对表达胃泌素释放肽受体（GRPR）的癌症进行检测、成像、诊断、靶向、治疗等的探针。例如，这种探针可以是与可检测标签连接的分子，这些标签最好是适合通过伽马成像和 SPECT 或正电子发射断层扫描（PET）或磁共振成像（MRI）或荧光光谱或光学成像方法进行检测的分子。
• Radiolabeled GRPR-Antagonists for Diagnostic Imaging and Treatment of GRPR-Positive Cancer
  申请人：Advanced Accelerator Applications International SA

  公开号：US20210346529A1

  公开（公告）日：2021-11-11

  The present invention relates to probes for use in the detection, imaging, diagnosis, targeting, treatment, etc. of cancers expressing the gastrin releasing peptide receptor (GRPR). For example, such probes may be molecules conjugated to detectable labels which are preferably moieties suitable for detection by gamma imaging and SPECT or by positron emission tomography (PET) or magnetic resonance imaging (MRI) or fluorescence spectroscopy or optical imaging methods.
• Pharmaceutical Composition Comprising a Radiolabeled GRPR Antagonist and a Surfactant
  申请人：Advanced Accelerator Applications International SA

  公开号：US20220008566A1

  公开（公告）日：2022-01-13

  The present disclosure relates to gastrin-releasing peptide receptor (GRPR) targeting radiopharmaceuticals and uses thereof. In particular, the present disclosure relates to a pharmaceutical composition comprising radiolabeled GRPR-antagonist and a surfactant. The present disclosure also relates to radiolabeled GRPR-antagonist for use in treating or preventing a cancer.