Evaluation of a Neurokinin-1 Receptor–Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging
- 16 Downloads
Neuroendocrine tumors (NETs) have reasonably high 5-year survival rates when diagnosed at an early stage but are significantly more lethal when discovered only after metastasis. Although several imaging modalities such as computed tomography (CT), positron emission tomography, and magnetic resonance imaging can detect neuroendocrine tumors, their high false positive rates suggest that more specific diagnostic tests are required. Targeted imaging agents such as Octreoscan® have met some of this need for improved specificity, but their inability to image poorly differentiated NETs suggests that improved NET imaging agents are still needed. Because neurokinin 1 receptors (NK1Rs) are widely over-expressed in neuroendocrine tumors, but show limited expression in healthy tissues, we have undertaken to develop an NK1R-targeted imaging agent for improved diagnosis and staging of neuroendocrine tumors.
A small molecule NK1R antagonist was conjugated via a flexible spacer to a Tc-99m chelating peptide. After complexation with Tc-99m, binding of the conjugate to human embryonic kidney (HEK293) cells transfected with the human NK1R was evaluated as a function of radioimaging agent concentration. In vivo imaging of HEK293-NK1R tumor xenografts in mice was also performed by single-photon emission computed tomography/computed tomography (γ-SPECT/CT), and the distribution of the conjugate in various tissues was quantified by tissue resection and γ-counting.
NK1R-targeted Tc-99m-based radioimaging agent displayed excellent affinity (Kd = 16.8 nM) and specificity for HEK293-NK1R tumor xenograft. SPECT/CT analysis of tumor-bearing mice demonstrated significant tumor uptake and high tumor to background ratio as early as 2 h post injection.
The excellent tumor contrast afforded by our NK1R-targeted radioimaging agent exhibits properties that could improve early diagnosis and staging of many neuroendocrine tumors.
Key wordsNonpeptidic ligand Ligand-targeted imaging agent Radioimaging of cancer Neurokinin receptor–targeted imaging Neuroendocrine tumor diagnosis and staging
HEK293 cells transduced with NK1R were a gift from Dr. Steven Douglas, Children’s Hospital of Philadelphia, Philadelphia, PA. We would like to offer thanks to Dr. Le-Cun Xu, Endocyte Inc. (West Lafayette, IN) and Jyoti Roy for their help with radio-HPLC detection of the radioimaging agent and animal surgeries, respectively. We would also like to thank John L Harwood and Karl V Wood for use of the NMR and mass spectrometry facilities, respectively.
This research work was supported by funding from Endocyte Inc. (West Lafayette, IN).
Compliance and Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 1.Lee LS (2010) Diagnosis of pancreatic neuroendocrine tumors and the role of endoscopic ultrasound. Gastroenterol Hepatol 6:520–522Google Scholar
- 8.Abgral R, Leboulleux S, Déandreis D, Aupérin A, Lumbroso J, Dromain C, Duvillard P, Elias D, de Baere T, Guigay J, Ducreux M, Schlumberger M, Baudin E (2011) Performance of 18fluorodeoxyglucose-positron emission tomography and somatostatin receptor scintigraphy for high Ki67 (≥ 10%) well-differentiated endocrine carcinoma staging. J Clin Endocrinol Metab 96:665–671CrossRefGoogle Scholar
- 10.Krenning EP, Bakker WH, Kooij PPM, Breeman WA, Oei HY, de Jong M, Reubi JC, Visser TJ, Bruns C, Kwekkeboom DJ (1992) Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide. J Nucl Med 33:652–658Google Scholar
- 11.Deppen SA, Liu E, Blume JD, Clanton J, Shi C, Jones-Jackson LB, Lakhani V, Baum RP, Berlin J, Smith GT, Graham M, Sandler MP, Delbeke D, Walker RC (2016) Safety and efficacy of 68Ga-DOTATATE PET/CT for diagnosis, staging, and treatment management of neuroendocrine tumors. Safety and efficacy of 68Ga-DOTATATE PET/CT for diagnosis, staging, and treatment management of neuroendocrine tumors. J Nucl Med 57:708–714CrossRefGoogle Scholar
- 12.Putzer D, Gabriel M, Henninger B, Kendler D, Uprimny C, Dobrozemsky G, Decristoforo C, Bale RJ, Jaschke W, Virgolini IJ (2009) Bone metastases in patients with neuroendocrine tumor: 68Ga-DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphy. J Nucl Med 50:1214–1221CrossRefGoogle Scholar
- 13.Munoz M, Covenas R (2010) Neurokinin-1 receptor: a new promising target in the treatment of cancer. Discov Med 10:305–313Google Scholar
- 17.Mantyh PW (2002) Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 63:6–10Google Scholar
- 18.Mozaffari S, Erfani M, Beiki D, Johari Daha F, Kobarfard F, Balalaie S, Fallahi B (2015) Synthesis and preliminary evaluation of a new 99mTc labeled substance P analogue as a potential tumor imaging agent. Iran J Pharm Res 14:97–110Google Scholar
- 19.de Araújo EB, Pujatti PB, Barrio O, Caldeira JS, Suzuki MF, Mengatti J (2010) Radiolabeling of substance P with lutetium-177 and biodistribution study in AR42J pancreatic tumor xenografted nude mice. Cell Mol Biol 56:12–17Google Scholar
- 32.Hillery AM, Lloyd AW, Swarbrick J (2002) Drug delivery and targeting: for pharmacists and pharmaceutical scientists. London: Taylor & FrancisGoogle Scholar