Synthesis and evaluation of a radiometal-labeled macrocyclic chelator-derivatised thymidine analog.
Identifieur interne : 002882 ( Main/Exploration ); précédent : 002881; suivant : 002883Synthesis and evaluation of a radiometal-labeled macrocyclic chelator-derivatised thymidine analog.
Auteurs : RBID : pubmed:16631084English descriptors
- KwdEn :
- Chelating Agents (chemistry), Gallium Radioisotopes (pharmacokinetics), HL-60 Cells (drug effects), Heterocyclic Compounds, 1-Ring (chemical synthesis), Heterocyclic Compounds, 1-Ring (pharmacokinetics), Humans, Indium Radioisotopes (pharmacokinetics), Ligands, Lymphoma, B-Cell (metabolism), Phosphorylation, Substrate Specificity, Thymidine (chemical synthesis), Thymidine (pharmacokinetics), Thymidine Kinase (metabolism), Tumor Cells, Cultured.
- MESH :
- chemical , chemical synthesis : Heterocyclic Compounds, 1-Ring, Thymidine.
- chemical , chemistry : Chelating Agents.
- chemical , metabolism : Thymidine Kinase.
- chemical , pharmacokinetics : Gallium Radioisotopes, Heterocyclic Compounds, 1-Ring, Indium Radioisotopes, Thymidine.
- drug effects : HL-60 Cells.
- metabolism : Lymphoma, B-Cell.
- Humans, Ligands, Phosphorylation, Substrate Specificity, Tumor Cells, Cultured.
Abstract
Several radiolabeled thymidine analogs as metabolic probes of cell proliferation were developed specifically addressing DNA synthesis. Thymidine analogs containing carboranylalkyl groups for neutron capture therapy at the N-3 position were found to be good substrates for cytosolic thymidine kinase 1 (TK1). According to this approach, a DO3A macrocycle in N-3 position was attached to thymidine. The 3-DO3A thymidine analog was labeled with 68Ga and 111In. Different lipophilicities of the corresponding radiometal-thymidines were detected via RP-HPLC. [111In]DO3A-thymidine ([111In]D3T) was evaluated for cellular uptake in different cell lines (HL60 and DoHH2). Cellular uptake was low in both cell lines. Phosphorylation of the radioconjugates by TK1 was negligible. Although stable complexation of radiometals to thymidine was obtained, introduction of the macrocycle DO3A reduced the affinity to cytosolic TK1 drastically. Low cellular uptake can be ascribed to missing substrate specificity of [111In]DO3A-thymidine for TK1. The absence of substrate specificity may be due to the bulky macrocyclic chelator and partial charges remaining on the coordination sphere due to a more complex solution structure.
DOI: 10.1016/j.nucmedbio.2005.12.010
PubMed: 16631084
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Synthesis and evaluation of a radiometal-labeled macrocyclic chelator-derivatised thymidine analog.</title><author><name sortKey="Schmid, Michaela" uniqKey="Schmid M">Michaela Schmid</name><affiliation wicri:level="3"><nlm:affiliation>Department of Nuclear Medicine, University Hospital Ulm, 89081 Ulm, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Nuclear Medicine, University Hospital Ulm, 89081 Ulm</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Ulm</settlement></placeName></affiliation></author><author><name sortKey="Neumaier, Bernd" uniqKey="Neumaier B">Bernd Neumaier</name></author><author><name sortKey="Vogg, Andreas T J" uniqKey="Vogg A">Andreas T J Vogg</name></author><author><name sortKey="Wczasek, Katrin" uniqKey="Wczasek K">Katrin Wczasek</name></author><author><name sortKey="Friesen, Claudia" uniqKey="Friesen C">Claudia Friesen</name></author><author><name sortKey="Mottaghy, Felix M" uniqKey="Mottaghy F">Felix M Mottaghy</name></author><author><name sortKey="Buck, Andreas K" uniqKey="Buck A">Andreas K Buck</name></author><author><name sortKey="Reske, Sven N" uniqKey="Reske S">Sven N Reske</name></author></titleStmt><publicationStmt><date when="2006">2006</date><idno type="doi">10.1016/j.nucmedbio.2005.12.010</idno><idno type="RBID">pubmed:16631084</idno><idno type="pmid">16631084</idno><idno type="wicri:Area/Main/Corpus">002B85</idno><idno type="wicri:Area/Main/Curation">002B85</idno><idno type="wicri:Area/Main/Exploration">002882</idno></publicationStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Chelating Agents (chemistry)</term><term>Gallium Radioisotopes (pharmacokinetics)</term><term>HL-60 Cells (drug effects)</term><term>Heterocyclic Compounds, 1-Ring (chemical synthesis)</term><term>Heterocyclic Compounds, 1-Ring (pharmacokinetics)</term><term>Humans</term><term>Indium Radioisotopes (pharmacokinetics)</term><term>Ligands</term><term>Lymphoma, B-Cell (metabolism)</term><term>Phosphorylation</term><term>Substrate Specificity</term><term>Thymidine (chemical synthesis)</term><term>Thymidine (pharmacokinetics)</term><term>Thymidine Kinase (metabolism)</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Heterocyclic Compounds, 1-Ring</term><term>Thymidine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Chelating Agents</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Thymidine Kinase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Gallium Radioisotopes</term><term>Heterocyclic Compounds, 1-Ring</term><term>Indium Radioisotopes</term><term>Thymidine</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HL-60 Cells</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lymphoma, B-Cell</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Ligands</term><term>Phosphorylation</term><term>Substrate Specificity</term><term>Tumor Cells, Cultured</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Several radiolabeled thymidine analogs as metabolic probes of cell proliferation were developed specifically addressing DNA synthesis. Thymidine analogs containing carboranylalkyl groups for neutron capture therapy at the N-3 position were found to be good substrates for cytosolic thymidine kinase 1 (TK1). According to this approach, a DO3A macrocycle in N-3 position was attached to thymidine. The 3-DO3A thymidine analog was labeled with 68Ga and 111In. Different lipophilicities of the corresponding radiometal-thymidines were detected via RP-HPLC. [111In]DO3A-thymidine ([111In]D3T) was evaluated for cellular uptake in different cell lines (HL60 and DoHH2). Cellular uptake was low in both cell lines. Phosphorylation of the radioconjugates by TK1 was negligible. Although stable complexation of radiometals to thymidine was obtained, introduction of the macrocycle DO3A reduced the affinity to cytosolic TK1 drastically. Low cellular uptake can be ascribed to missing substrate specificity of [111In]DO3A-thymidine for TK1. The absence of substrate specificity may be due to the bulky macrocyclic chelator and partial charges remaining on the coordination sphere due to a more complex solution structure.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">16631084</PMID><DateCreated><Year>2006</Year><Month>04</Month><Day>24</Day></DateCreated><DateCompleted><Year>2006</Year><Month>12</Month><Day>18</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">0969-8051</ISSN><JournalIssue CitedMedium="Print"><Volume>33</Volume><Issue>3</Issue><PubDate><Year>2006</Year><Month>Apr</Month></PubDate></JournalIssue><Title>Nuclear medicine and biology</Title><ISOAbbreviation>Nucl. Med. Biol.</ISOAbbreviation></Journal><ArticleTitle>Synthesis and evaluation of a radiometal-labeled macrocyclic chelator-derivatised thymidine analog.</ArticleTitle><Pagination><MedlinePgn>359-66</MedlinePgn></Pagination><Abstract><AbstractText>Several radiolabeled thymidine analogs as metabolic probes of cell proliferation were developed specifically addressing DNA synthesis. Thymidine analogs containing carboranylalkyl groups for neutron capture therapy at the N-3 position were found to be good substrates for cytosolic thymidine kinase 1 (TK1). According to this approach, a DO3A macrocycle in N-3 position was attached to thymidine. The 3-DO3A thymidine analog was labeled with 68Ga and 111In. Different lipophilicities of the corresponding radiometal-thymidines were detected via RP-HPLC. [111In]DO3A-thymidine ([111In]D3T) was evaluated for cellular uptake in different cell lines (HL60 and DoHH2). Cellular uptake was low in both cell lines. Phosphorylation of the radioconjugates by TK1 was negligible. Although stable complexation of radiometals to thymidine was obtained, introduction of the macrocycle DO3A reduced the affinity to cytosolic TK1 drastically. Low cellular uptake can be ascribed to missing substrate specificity of [111In]DO3A-thymidine for TK1. The absence of substrate specificity may be due to the bulky macrocyclic chelator and partial charges remaining on the coordination sphere due to a more complex solution structure.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Schmid</LastName><ForeName>Michaela</ForeName><Initials>M</Initials><Affiliation>Department of Nuclear Medicine, University Hospital Ulm, 89081 Ulm, Germany.</Affiliation></Author><Author ValidYN="Y"><LastName>Neumaier</LastName><ForeName>Bernd</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Vogg</LastName><ForeName>Andreas T J</ForeName><Initials>AT</Initials></Author><Author ValidYN="Y"><LastName>Wczasek</LastName><ForeName>Katrin</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Friesen</LastName><ForeName>Claudia</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Mottaghy</LastName><ForeName>Felix M</ForeName><Initials>FM</Initials></Author><Author ValidYN="Y"><LastName>Buck</LastName><ForeName>Andreas K</ForeName><Initials>AK</Initials></Author><Author ValidYN="Y"><LastName>Reske</LastName><ForeName>Sven N</ForeName><Initials>SN</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType>Journal Article</PublicationType><PublicationType>Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2006</Year><Month>03</Month><Day>09</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Nucl Med Biol</MedlineTA><NlmUniqueID>9304420</NlmUniqueID><ISSNLinking>0969-8051</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>1,4,7-tris(tert-butylacetate)-1,4,7,10-tetraazacyclododecane ester</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Chelating Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Gallium Radioisotopes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Heterocyclic Compounds, 1-Ring</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Indium Radioisotopes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Ligands</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.21</RegistryNumber><NameOfSubstance>Thymidine Kinase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.21</RegistryNumber><NameOfSubstance>thymidine kinase 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>VC2W18DGKR</RegistryNumber><NameOfSubstance>Thymidine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName MajorTopicYN="N">Chelating Agents</DescriptorName><QualifierName MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Gallium Radioisotopes</DescriptorName><QualifierName MajorTopicYN="Y">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">HL-60 Cells</DescriptorName><QualifierName MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Heterocyclic Compounds, 1-Ring</DescriptorName><QualifierName MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Indium Radioisotopes</DescriptorName><QualifierName MajorTopicYN="Y">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Ligands</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Lymphoma, B-Cell</DescriptorName><QualifierName MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Phosphorylation</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Substrate Specificity</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Thymidine</DescriptorName><QualifierName MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName MajorTopicYN="Y">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Thymidine Kinase</DescriptorName><QualifierName MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Tumor Cells, Cultured</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2005</Year><Month>10</Month><Day>13</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2005</Year><Month>11</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2005</Year><Month>12</Month><Day>4</Day></PubMedPubDate><PubMedPubDate PubStatus="aheadofprint"><Year>2006</Year><Month>3</Month><Day>9</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>12</Month><Day>19</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pii">S0969-8051(05)00296-9</ArticleId><ArticleId IdType="doi">10.1016/j.nucmedbio.2005.12.010</ArticleId><ArticleId IdType="pubmed">16631084</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix 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