Evaluation of a Neurokinin-1 Receptor–Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging
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 r...
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| Veröffentlicht in: | Molecular imaging and biology 2020-04, Vol.22 (2), p.377-383 |
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| creator | Kanduluru, Ananda Kumar Srinivasarao, Madduri Wayua, Charity Low, Philip S. |
| description | 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 (
K
d
= 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. |
| doi_str_mv | 10.1007/s11307-019-01391-w |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2256099291</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2375514265</sourcerecordid><originalsourceid>FETCH-LOGICAL-c403t-e64fcb3dda87391e12428415fd82653da65e1ee4088d2754d26b4d3c482cfc6e3</originalsourceid><addsrcrecordid>eNp9kc9u1DAQxi1ERUvhBTggS1x6CfWM7fw5olVbKlUgoeVsee1JyHZjL3ZCxY134A37JGRJAYlDD5Ytze_7ZsYfY69AvAUhqvMMIEVVCGjmIxso7p6wE6hLUaAQ-HR-a1kWUEo8Zs9z3goBFaB8xo4lYIMN6BN2e_HN7iY79jHw2HLLP9CU4m0f-lAA_0SO9mNM9z9-rm3qaCTP1-S-BBr7aSiaZuCrGLZTZ0fibUyLmoKPLvWB-MoGR4lfD7brQ_eCHbV2l-nlw33KPl9erFfvi5uPV9erdzeFU0KOBZWqdRvpva2reSsCVFgr0K2vsdTS21ITEClR1x4rrTyWG-WlUzW61pUkT9nZ4rtP8etEeTRDnx3tdjZQnLJB1KVoDh8wo2_-Q7dxSmGezqCstAZ1aPkYhVqjRgUHL1wol2LOiVqzT_1g03cDwhwCM0tgZg7M_A7M3M2i1w_W02Yg_1fyJ6EZkAuQ51LoKP3r_YjtLyPooNw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2255252411</pqid></control><display><type>article</type><title>Evaluation of a Neurokinin-1 Receptor–Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Kanduluru, Ananda Kumar ; Srinivasarao, Madduri ; Wayua, Charity ; Low, Philip S.</creator><creatorcontrib>Kanduluru, Ananda Kumar ; Srinivasarao, Madduri ; Wayua, Charity ; Low, Philip S.</creatorcontrib><description>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 (
K
d
= 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.</description><identifier>ISSN: 1536-1632</identifier><identifier>EISSN: 1860-2002</identifier><identifier>DOI: 10.1007/s11307-019-01391-w</identifier><identifier>PMID: 31292915</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Animals ; Chelating Agents - chemistry ; Chelation ; Computation ; Computed tomography ; Conjugates ; Diagnosis ; Diagnostic systems ; False Positive Reactions ; Female ; HEK293 Cells ; Humans ; Imaging ; In vivo methods and tests ; Ligands ; Magnetic resonance imaging ; Medical diagnosis ; Medical imaging ; Medicine ; Medicine & Public Health ; Metastases ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neuroendocrine tumors ; Neuroendocrine Tumors - diagnostic imaging ; Neurokinin ; Neurokinin NK1 receptors ; Peptides - chemistry ; Photon emission ; Positron emission ; Positron emission tomography ; Radiology ; Receptors ; Receptors, Neurokinin-1 - chemistry ; Research Article ; Single photon emission computed tomography ; Single Photon Emission Computed Tomography Computed Tomography ; Somatostatin - analogs & derivatives ; Technetium ; Technetium - chemistry ; Technetium isotopes ; Tissues ; Tomography ; Tomography, X-Ray Computed ; Tumors ; Xenografts ; Xenotransplantation</subject><ispartof>Molecular imaging and biology, 2020-04, Vol.22 (2), p.377-383</ispartof><rights>World Molecular Imaging Society 2019</rights><rights>Molecular Imaging and Biology is a copyright of Springer, (2019). All Rights Reserved.</rights><rights>2019© World Molecular Imaging Society 2019</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c403t-e64fcb3dda87391e12428415fd82653da65e1ee4088d2754d26b4d3c482cfc6e3</citedby><cites>FETCH-LOGICAL-c403t-e64fcb3dda87391e12428415fd82653da65e1ee4088d2754d26b4d3c482cfc6e3</cites><orcidid>0000-0003-2669-8665</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11307-019-01391-w$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11307-019-01391-w$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31292915$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kanduluru, Ananda Kumar</creatorcontrib><creatorcontrib>Srinivasarao, Madduri</creatorcontrib><creatorcontrib>Wayua, Charity</creatorcontrib><creatorcontrib>Low, Philip S.</creatorcontrib><title>Evaluation of a Neurokinin-1 Receptor–Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging</title><title>Molecular imaging and biology</title><addtitle>Mol Imaging Biol</addtitle><addtitle>Mol Imaging Biol</addtitle><description>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 (
K
d
= 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.</description><subject>Animals</subject><subject>Chelating Agents - chemistry</subject><subject>Chelation</subject><subject>Computation</subject><subject>Computed tomography</subject><subject>Conjugates</subject><subject>Diagnosis</subject><subject>Diagnostic systems</subject><subject>False Positive Reactions</subject><subject>Female</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Imaging</subject><subject>In vivo methods and tests</subject><subject>Ligands</subject><subject>Magnetic resonance imaging</subject><subject>Medical diagnosis</subject><subject>Medical imaging</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Neoplasm Transplantation</subject><subject>Neuroendocrine tumors</subject><subject>Neuroendocrine Tumors - diagnostic imaging</subject><subject>Neurokinin</subject><subject>Neurokinin NK1 receptors</subject><subject>Peptides - chemistry</subject><subject>Photon emission</subject><subject>Positron emission</subject><subject>Positron emission tomography</subject><subject>Radiology</subject><subject>Receptors</subject><subject>Receptors, Neurokinin-1 - chemistry</subject><subject>Research Article</subject><subject>Single photon emission computed tomography</subject><subject>Single Photon Emission Computed Tomography Computed Tomography</subject><subject>Somatostatin - analogs & derivatives</subject><subject>Technetium</subject><subject>Technetium - chemistry</subject><subject>Technetium isotopes</subject><subject>Tissues</subject><subject>Tomography</subject><subject>Tomography, X-Ray Computed</subject><subject>Tumors</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>1536-1632</issn><issn>1860-2002</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9u1DAQxi1ERUvhBTggS1x6CfWM7fw5olVbKlUgoeVsee1JyHZjL3ZCxY134A37JGRJAYlDD5Ytze_7ZsYfY69AvAUhqvMMIEVVCGjmIxso7p6wE6hLUaAQ-HR-a1kWUEo8Zs9z3goBFaB8xo4lYIMN6BN2e_HN7iY79jHw2HLLP9CU4m0f-lAA_0SO9mNM9z9-rm3qaCTP1-S-BBr7aSiaZuCrGLZTZ0fibUyLmoKPLvWB-MoGR4lfD7brQ_eCHbV2l-nlw33KPl9erFfvi5uPV9erdzeFU0KOBZWqdRvpva2reSsCVFgr0K2vsdTS21ITEClR1x4rrTyWG-WlUzW61pUkT9nZ4rtP8etEeTRDnx3tdjZQnLJB1KVoDh8wo2_-Q7dxSmGezqCstAZ1aPkYhVqjRgUHL1wol2LOiVqzT_1g03cDwhwCM0tgZg7M_A7M3M2i1w_W02Yg_1fyJ6EZkAuQ51LoKP3r_YjtLyPooNw</recordid><startdate>20200401</startdate><enddate>20200401</enddate><creator>Kanduluru, Ananda Kumar</creator><creator>Srinivasarao, Madduri</creator><creator>Wayua, Charity</creator><creator>Low, Philip S.</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2669-8665</orcidid></search><sort><creationdate>20200401</creationdate><title>Evaluation of a Neurokinin-1 Receptor–Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging</title><author>Kanduluru, Ananda Kumar ; Srinivasarao, Madduri ; Wayua, Charity ; Low, Philip S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c403t-e64fcb3dda87391e12428415fd82653da65e1ee4088d2754d26b4d3c482cfc6e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Chelating Agents - chemistry</topic><topic>Chelation</topic><topic>Computation</topic><topic>Computed tomography</topic><topic>Conjugates</topic><topic>Diagnosis</topic><topic>Diagnostic systems</topic><topic>False Positive Reactions</topic><topic>Female</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Imaging</topic><topic>In vivo methods and tests</topic><topic>Ligands</topic><topic>Magnetic resonance imaging</topic><topic>Medical diagnosis</topic><topic>Medical imaging</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neoplasm Transplantation</topic><topic>Neuroendocrine tumors</topic><topic>Neuroendocrine Tumors - diagnostic imaging</topic><topic>Neurokinin</topic><topic>Neurokinin NK1 receptors</topic><topic>Peptides - chemistry</topic><topic>Photon emission</topic><topic>Positron emission</topic><topic>Positron emission tomography</topic><topic>Radiology</topic><topic>Receptors</topic><topic>Receptors, Neurokinin-1 - chemistry</topic><topic>Research Article</topic><topic>Single photon emission computed tomography</topic><topic>Single Photon Emission Computed Tomography Computed Tomography</topic><topic>Somatostatin - analogs & derivatives</topic><topic>Technetium</topic><topic>Technetium - chemistry</topic><topic>Technetium isotopes</topic><topic>Tissues</topic><topic>Tomography</topic><topic>Tomography, X-Ray Computed</topic><topic>Tumors</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kanduluru, Ananda Kumar</creatorcontrib><creatorcontrib>Srinivasarao, Madduri</creatorcontrib><creatorcontrib>Wayua, Charity</creatorcontrib><creatorcontrib>Low, Philip S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular imaging and biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kanduluru, Ananda Kumar</au><au>Srinivasarao, Madduri</au><au>Wayua, Charity</au><au>Low, Philip S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of a Neurokinin-1 Receptor–Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging</atitle><jtitle>Molecular imaging and biology</jtitle><stitle>Mol Imaging Biol</stitle><addtitle>Mol Imaging Biol</addtitle><date>2020-04-01</date><risdate>2020</risdate><volume>22</volume><issue>2</issue><spage>377</spage><epage>383</epage><pages>377-383</pages><issn>1536-1632</issn><eissn>1860-2002</eissn><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 (
K
d
= 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.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>31292915</pmid><doi>10.1007/s11307-019-01391-w</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-2669-8665</orcidid></addata></record> |
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| ispartof | Molecular imaging and biology, 2020-04, Vol.22 (2), p.377-383 |
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| subjects | Animals Chelating Agents - chemistry Chelation Computation Computed tomography Conjugates Diagnosis Diagnostic systems False Positive Reactions Female HEK293 Cells Humans Imaging In vivo methods and tests Ligands Magnetic resonance imaging Medical diagnosis Medical imaging Medicine Medicine & Public Health Metastases Mice Mice, Nude Neoplasm Transplantation Neuroendocrine tumors Neuroendocrine Tumors - diagnostic imaging Neurokinin Neurokinin NK1 receptors Peptides - chemistry Photon emission Positron emission Positron emission tomography Radiology Receptors Receptors, Neurokinin-1 - chemistry Research Article Single photon emission computed tomography Single Photon Emission Computed Tomography Computed Tomography Somatostatin - analogs & derivatives Technetium Technetium - chemistry Technetium isotopes Tissues Tomography Tomography, X-Ray Computed Tumors Xenografts Xenotransplantation |
| title | Evaluation of a Neurokinin-1 Receptor–Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging |
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