Synthesis and Preliminary Evaluation of a New 99mTc Labeled Substance P Analogue as a Potential Tumor Imaging Agent

Document Type: Research article

Authors

1 Department of Radiopharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

2 Nuclear Science Research School, Nuclear Science and Technology Research Institute (NSTRI), Atomic Energy Organization of Iran (AEOI), Tehran, Iran

3 Research Center for Nuclear Medicine, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

5 Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran, Iran

Abstract

Neurokinin 1 receptors (NK1R) are overexpressed on several types of important human cancer cells. Substance P (SP) is the most specific endogenous ligand known for NK1Rs. Accordingly, a new SP analogue was synthesized and evaluated for detection of NK1R positive tumors. [6-hydrazinopyridine-3-carboxylic acid (HYNIC)-Tyr8-Met(O)11-SP] was synthesized and radiolabeled with 99mTc using ethylenediamine-N,N'-diacetic acid (EDDA) and Tricine as coligands. Common physicochemichal properties of radioconjugate were studied and in vitro cell line biological tests were accomplished to determine the receptor mediated characteristics. In vivo biodistribution in normal and tumor bearing nude mice was also assessed. The cold peptide was prepared in high purity (>99%) and radiolabeled with 99mTc at high specific activities (84-112GBq/µmol) with an acceptable labeling yield (>95%). The radioconjugate was stable in vitro in the presence of human serum and showed 44% protein binding to human serum albumin. In vitro cell line studies on U373MG cells showed an acceptable uptake up to 4.91 ± 0.22% with the ratio of 60.21 ± 1.19% for its specific fraction and increasing specific internalization during 4h. Receptor binding assays on U373MG cells indicated a mean Kd of 2.46 ± 0.43 nM and Bmax of 128925 ± 8145 sites/cell. In vivo investigations determined the specific tumor uptake in 3.36 percent of injected dose per gram (%ID/g) for U373MG cells and noticeable accumulations of activity in the intestines and lung. Predominant renal excretion pathway was demonstrated.
Therefore, this new radiolabeled peptide could be a promising radiotracer for detection of NK1R positive primary or secondary tumors.

Keywords

Iranian Journal of Pharmaceutical Research

Volume 14, Issue 1
Winter 2015
Pages 97-110

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