Ananda Kumar Kanduluru1, Madduri Srinivasarao2, Charity Wayua2, Philip S Low3,4. 1. On Target Laboratories Inc., West Lafayette, IN, 47906, USA. 2. Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA. 3. On Target Laboratories Inc., West Lafayette, IN, 47906, USA. plow@purdue.edu. 4. Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA. plow@purdue.edu.
Abstract
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.
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 humanembryonic kidney (HEK293) cells transfected with the humanNK1R was evaluated as a function of radioimaging agent concentration. In vivo imaging of HEK293-NK1Rtumor 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-NK1Rtumor 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.
Entities:
Keywords:
Ligand-targeted imaging agent; Neuroendocrine tumor diagnosis and staging; Neurokinin receptor–targeted imaging; Nonpeptidic ligand; Radioimaging of cancer
Authors: Paweł K Halik; Przemysław Koźmiński; Joanna Matalińska; Piotr F J Lipiński; Aleksandra Misicka; Ewa Gniazdowska Journal: Pharmaceutics Date: 2022-03-10 Impact factor: 6.321