作者: Fu, Jingjing ; Wang, Feng ; Hodolic, Marina ; Shi, Liang ; You, Qinqin ; Wu, Wenyu ; Yu, Fei ; Guo, Hongqian ; Ai, Shuyue ; Shao, Guoqiang ; Bu, Ting ; Zhang, Pengjun

Prostate-specific membrane antigen (PSMA)-negative neuroendocrine prostate cancer (PCa) is a subtype of PCa likely to be lethal, with limited clinical diagnostic and therapeutic options. High expression of neurotensin receptor subtype 1 (NTR1) is associated with neuroendocrine differentiation of PCa, which makes NTR1 a potential target for neuroendocrine PCa. In this study, the NTR1-targeted tracer ⁶⁸Ga-DOTA-NT-20.3 was synthesized, and its affinity to androgen-dependent (LNCap) and androgen-independent (PC3) xenografts was determined. Methods: ⁶⁸Ga-DOTA-NT-20.3 was labeled using an automated synthesizer module, and its stability, labeling yield, and radiochemical purity were analyzed by radio-high-performance liquid chromatography. Receptor binding affinity was evaluated in NTR1-positive PC3 cells by a competitive binding assay. The biodistribution of ⁶⁸Ga-DOTA-NT-20.3 in vivo was evaluated in PC3 and LNCap xenografts by small-animal PET imaging. NTR1 expression was identified by immunohistochemistry and immunofluorescence evaluation. Results: ⁶⁸Ga-DOTA-NT-20.3 was synthesized successfully, with a yield of 88.07% ± 1.26%, radiochemical purity of at least 99%, and favorable stability. The NTR1 affinity (half-maximal inhibitory concentration) for ⁶⁸Ga-DOTA-NT-20.3 was 7.59 ± 0.41 nM. Small-animal PET/CT of PC3 xenograft animals showed high-contrast images with intense tumor uptake, which revealed specific NTR1 expression. The tumors showed significant radioactivity (4.95 ± 0.67 percentage injected dose per gram of tissue [%ID/g]) at 1 h, which fell to 1.95 ± 0.17 %ID/g (P < 0.01, t = 8.72) after specific blockage by neurotensin. LNCap xenografts had no significant accumulation (0.81 ± 0.06 %ID/g) of ⁶⁸Ga-DOTA-NT-20.3 at 1 h. In contrast, ⁶⁸Ga-PSMA-11 was concentrated mainly in LNCap xenografts (8.60 ± 2.11 %ID/g), with no significant uptake in PC3 tumors (0.53 ± 0.05 %ID/g), consistent with the in vitro immunohistochemistry findings. Biodistribution evaluation showed rapid clearance from the blood and main organs (brain, heart, lung, liver, muscle, and bone), with significantly high tumor-to-liver (4.41 ± 0.73) and tumor-to-muscle (12.34 ± 1.32) ratios at 60 min after injection. Conclusion: ⁶⁸Ga-DOTA-NT-20.3 can be efficiently prepared with a high yield and high radiochemical purity. Its favorable biodistribution and prominent NTR1 affinity make ⁶⁸Ga-DOTA-NT-20.3 a potential radiopharmaceutical for the detection of PSMA-negative PCa and identification of neuroendocrine differentiation.

2021-04-01·European Journal of Nuclear Medicine and Molecular Imaging1区 · 医学

Safety and tolerability of 68Ga-NT-20.3, a radiopharmaceutical for targeting neurotensin receptors, in patients with pancreatic ductal adenocarcinoma: the first in-human use

1区 · 医学

Article

作者: Zhao, Zhenyu ; Virgolini, Irene ; Yu, Fei ; Wu, Wen-Yu ; Wang, Feng ; Hodolic, Marina

INTRODUCTIONOver the last decades, multiple peptide receptors were recognized as potential diagnostic and therapeutic targets in nuclear medicine. ⁶⁸Ga-NT-20.3 radiopharmaceutical has been developed for diagnosis of neurotensin receptors. High neurotensin receptor expression has been observed in pancreatic ductal adenocarcinoma as well as various malignancies. Until now, ⁶⁸Ga-labelled NT ligand was successfully applied in in vitro as well as in animal model. Our study is the first in-human study on safety and tolerability of ⁶⁸Ga-NT-20.3.METHODSSubjects were intravenously injected with 2.5 MBq of ⁶⁸Ga-DOTA-NT-20.3 per kilogramme of body weight, and series of PET images were acquired at 5-25 min, 25-45 min, 45-65 min, and 65-85 min after ⁶⁸Ga-NT-20.3 injection. Vital parameters are as follows: systolic and diastolic blood pressure (mmHg), heart rate (heart beat/min), respiratory rate (number of breaths/min), ECG, and body temperature (°C) were checked before, immediately after, and 3 h after ⁶⁸Ga-NT-20.3 injection. The organ-absorbed doses were calculated for the self-dose and cross-dose from each organ region using the OLINDA/EXM version 2.1 software.RESULTS AND CONCLUSIONThe results from this small trial demonstrate that PET radiopharmaceutical ⁶⁸Ga-NT-20.3 is safe and well tolerated.

2019-06-03·Molecular Pharmaceutics2区 · 医学

Preclinical Evaluation of ⁶⁸Ga-DOTA-NT-20.3: A Promising PET Imaging Probe To Discriminate Human Pancreatic Ductal Adenocarcinoma from Pancreatitis

2区 · 医学

Article

作者: Provost, Claire ; Talbot, Jean-Noël ; Prignon, Aurélie ; Forgez, Patricia ; Couvelard, Anne ; Gruaz-Guyon, Anne ; Alshoukr, Faisal ; Barbet, Jacques ; Wendum, Dominique

Neurotensin receptor 1 (NTSR1) is overexpressed in human pancreatic ductal adenocarcinoma (PDAC). Specific noninvasive positron-emission tomography (PET) imaging probes may improve the diagnostic accuracy and the monitoring of therapy for patients with PDAC. Here, we report the use of the ⁶⁸Ga-labeled neurotensin (NTS) analogue DOTA-NT-20.3 to image human PDAC in animal models and to discriminate tumors from pancreatitis. In addition to the preclinical study, two tissue microarray slides, constructed by small core biopsies (2-5) from standard paraffin-embedded tumor tissues, were used to confirm the high (78%) positivity rate of NTSR1 expression in human PDAC. PET imaging, biodistribution, blocking, and histology studies were performed in subcutaneous AsPC-1 pancreatic tumor-bearing mice. ⁶⁸Ga-DOTA-NT-20.3 PET images showed rapid tumor uptake and high contrast between the tumor and background with a fast blood clearance and a moderate accumulation in the kidneys. Ex vivo biodistribution showed low uptake in normal pancreas (0.22% IA/g) and in the remaining organs at 1 h postinjection, kidney retention (5.38 ± 0.54% IA/g), and fast clearance from blood and confirmed high uptake in tumors (5.28 ± 0.93% IA/g), leading to a tumor-to-blood ratio value of 6 at 1 h postinjection. The significant decrease of tumor uptake in a blocking study demonstrated the specificity of ⁶⁸Ga-DOTA-N-T20.3 to target NTSR1 in vivo. PET imaging was also conducted in an orthotopic xenograft model that allows tumors to grow in their native microenvironment and in an experimental pancreatitis model generated by caerulein injections. As opposed to 2-[¹⁸F]fluoro-deoxyglucose, ⁶⁸Ga-DOTA-NT-20.3 distinguishes PDAC from pancreatitis. Thus, ⁶⁸Ga-DOTA-NT-20.3 is a promising PET imaging probe for imaging PDAC in humans.

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适应症	最高研发状态	国家/地区	公司	日期
前列腺癌	临床前	中国	南京医科大学	2023-05-25
恶性胸膜间皮瘤	临床前	意大利	IRCCS Policlinico San Donato	2018-09-15
恶性胸膜间皮瘤	临床前	奥地利	Iason Sp. z o. o	2018-09-15