99mTc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen

Xiaoping Xu; Jianping Zhang; Silong Hu; Simin He; Xiao Bao; Guang Ma; Jianmin Luo; Jingyi Cheng; Yingjian Zhang

doi:10.1016/j.nucmedbio.2017.01.010

^99mTc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen

Nucl Med Biol. 2017 May:48:69-75. doi: 10.1016/j.nucmedbio.2017.01.010. Epub 2017 Jan 28.

Authors

Xiaoping Xu¹, Jianping Zhang¹, Silong Hu², Simin He³, Xiao Bao³, Guang Ma³, Jianmin Luo³, Jingyi Cheng¹, Yingjian Zhang¹

Affiliations

¹ Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China; Shanghai Proton and Heavy Ion Center, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
² Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China; Shanghai Proton and Heavy Ion Center, Fudan University Shanghai Cancer Center, Shanghai 200032, China. Electronic address: husilong0071@163.com.
³ Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Biomedical Imaging, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China.

PMID: 28273495
DOI: 10.1016/j.nucmedbio.2017.01.010

Abstract

Introduction: Prostate-specific membrane antigen (PSMA) is a well-established target in the development of radiopharmaceuticals for the diagnosis and therapy of prostate cancer (PCa). In this study, we evaluated a novel ^99mTc-labeled small molecular inhibitor of PSMA.

Methods: This new small-molecular inhibitor of PSMA, 6-hydrazinonicotinate-Aminocaproic acid-Lysine-Urea-Glutamate (HYNIC-ALUG) was radiolabeled by ^99mTc and was evaluated both in vitro and in vivo using PCa models (PC-3 and LNCaP). Radiation dosimetry was assessed in mice.

Results: ^99mTc-HYNIC-ALUG showed excellent stability in different media. A cell assay preliminarily displayed its specificity for PSMA. The inhibitor showed good pharmacokinetics making it suitable for in vivo imaging. PC-3-derived tumors showed no obvious radioactive uptake; however, the LNCaP-derived tumors showed very high radioactive uptake which was significantly decreased by the selective PSMA inhibitor 2-PMPA. Biodistribution in LNCaP xenografts showed an optimum tumor-to-blood ratio of 24.23±3.54 at 2h. Tumor uptake was also decreased in the inhibition experiment with 2-PMPA (19.45±2.14%ID/g versus 1.42±0.15%ID/g at 2h). The effective dose of the ^99mTc-HYNIC-ALUG was 8.4E-04mSv/MBq.

Conclusions: A new ^99mTc-labeled PSMA inhibitor with specific accumulation in PSMA-positive tumors and low background in other organs was synthesized. The radiopharmaceutical also showed very low radiation dosimetry. This agent may significantly improve the diagnosis, staging, and subsequent monitoring of therapeutic effects in PCa patients.

Keywords: (99m)Tc-radiolabeled agents; Nano-SPECT imaging; PSMA inhibitor; Prostate cancer; Radiation dosimetry.

MeSH terms

Animals
Antigens, Surface
Biological Transport
Cell Line, Tumor
Drug Stability
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology
Ethanol / chemistry
Glutamate Carboxypeptidase II / antagonists & inhibitors*
Hydrazines / chemistry*
Isotope Labeling
Male
Mice
Nicotinic Acids / chemistry*
Prostatic Neoplasms / diagnostic imaging
Prostatic Neoplasms / pathology
Single Photon Emission Computed Tomography Computed Tomography
Technetium*
Tissue Distribution
Urea / chemistry*
Urea / metabolism
Urea / pharmacokinetics
Urea / pharmacology
Water / chemistry

Substances

6-hydrazinopyridine-3-carboxylic acid
Antigens, Surface
Enzyme Inhibitors
Hydrazines
Nicotinic Acids
Water
Ethanol
Technetium
Urea
FOLH1 protein, human
Glutamate Carboxypeptidase II