TY - JOUR
T1 - Evaluation of a Neurokinin-1 Receptor–Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging
AU - Kanduluru, Ananda Kumar
AU - Srinivasarao, Madduri
AU - Wayua, Charity
AU - Low, Philip S.
N1 - Funding Information:
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.
Funding Information:
This research work was supported by funding from Endocyte Inc. (West Lafayette, IN). Acknowledgments
Publisher Copyright:
© 2019, World Molecular Imaging Society.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - Purpose: 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. Procedure: 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. Results: 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. Conclusion: The excellent tumor contrast afforded by our NK1R-targeted radioimaging agent exhibits properties that could improve early diagnosis and staging of many neuroendocrine tumors.
AB - Purpose: 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. Procedure: 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. Results: 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. Conclusion: The excellent tumor contrast afforded by our NK1R-targeted radioimaging agent exhibits properties that could improve early diagnosis and staging of many neuroendocrine tumors.
KW - Ligand-targeted imaging agent
KW - Neuroendocrine tumor diagnosis and staging
KW - Neurokinin receptor–targeted imaging
KW - Nonpeptidic ligand
KW - Radioimaging of cancer
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U2 - 10.1007/s11307-019-01391-w
DO - 10.1007/s11307-019-01391-w
M3 - Article
C2 - 31292915
AN - SCOPUS:85068909533
SN - 1536-1632
VL - 22
SP - 377
EP - 383
JO - Molecular Imaging and Biology
JF - Molecular Imaging and Biology
IS - 2
ER -