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Design, synthesis and evaluation of (18)F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging.

Abstract Carbonic anhydrase IX (CA-IX) is a marker for tumor hypoxia, and its expression is negatively correlated with patient survival. CA-IX represents a potential target for eliminating hypoxic cancers. We synthesized fluorinated cationic sulfonamide inhibitors 1-3 designed to target CA-IX. The binding affinity for CA-IX ranged from 0.22 to 0.96 μM. We evaluated compound 2 as a diagnostic PET imaging agent. Compound 2 was radiolabeled with (18)F in 10 ± 4% decay-corrected radiochemical yield with 85.1 ± 70.3 GBq/μmol specific activity and >98% radiochemical purity. (18)F-labeled 2 was stable in mouse plasma at 37 °C after 1 h incubation. PET/CT imaging was conducted at 1 h post-injection in a human colorectal cancer xenograft model. (18)F-labeled 2 cleared through hepatobiliary and renal pathways. Tumor uptake was approximately 0.41 ± 0.06% ID/g, with a tumor-to-muscle ratio of 1.99 ± 0.25. Subsequently, tumor xenografts were visualized with moderate contrast. This study demonstrates the use of a cationic motif for conferring isoform selectively for CA-IX imaging agents.
PMID
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Authors

Mayor MeshTerms

Drug Design

Keywords

Carbonic anhydrase IX

fluorine-18

molecular imaging

positron emission tomography

Journal Title journal of enzyme inhibition and medicinal chemistry
Publication Year Start




PMID- 28385087
OWN - NLM
STAT- MEDLINE
DA  - 20170407
DCOM- 20170420
LR  - 20170420
IS  - 1475-6374 (Electronic)
IS  - 1475-6366 (Linking)
VI  - 32
IP  - 1
DP  - 2017 Dec
TI  - Design, synthesis and evaluation of 18F-labeled cationic carbonic anhydrase IX
      inhibitors for PET imaging.
PG  - 722-730
LID - 10.1080/14756366.2017.1308928 [doi]
AB  - Carbonic anhydrase IX (CA-IX) is a marker for tumor hypoxia, and its expression
      is negatively correlated with patient survival. CA-IX represents a potential
      target for eliminating hypoxic cancers. We synthesized fluorinated cationic
      sulfonamide inhibitors 1-3 designed to target CA-IX. The binding affinity for
      CA-IX ranged from 0.22 to 0.96 muM. We evaluated compound 2 as a diagnostic PET
      imaging agent. Compound 2 was radiolabeled with 18F in 10 +/- 4% decay-corrected 
      radiochemical yield with 85.1 +/- 70.3 GBq/mumol specific activity and >98%
      radiochemical purity. 18F-labeled 2 was stable in mouse plasma at 37 degrees C
      after 1 h incubation. PET/CT imaging was conducted at 1 h post-injection in a
      human colorectal cancer xenograft model. 18F-labeled 2 cleared through
      hepatobiliary and renal pathways. Tumor uptake was approximately 0.41 +/- 0.06%
      ID/g, with a tumor-to-muscle ratio of 1.99 +/- 0.25. Subsequently, tumor
      xenografts were visualized with moderate contrast. This study demonstrates the
      use of a cationic motif for conferring isoform selectively for CA-IX imaging
      agents.
FAU - Zhang, Zhengxing
AU  - Zhang Z
AD  - a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British
      Columbia , Canada.
FAU - Lau, Joseph
AU  - Lau J
AD  - a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British
      Columbia , Canada.
FAU - Zhang, Chengcheng
AU  - Zhang C
AD  - a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British
      Columbia , Canada.
FAU - Colpo, Nadine
AU  - Colpo N
AD  - a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British
      Columbia , Canada.
FAU - Nocentini, Alessio
AU  - Nocentini A
AD  - b Department of Neurofarba, Section of Pharmaceutical and Nutriceutical Sciences 
      , Universita Degli Studi Di Firenze , Florence , Italy.
FAU - Supuran, Claudiu T
AU  - Supuran CT
AD  - b Department of Neurofarba, Section of Pharmaceutical and Nutriceutical Sciences 
      , Universita Degli Studi Di Firenze , Florence , Italy.
FAU - Benard, Francois
AU  - Benard F
AD  - a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British
      Columbia , Canada.
AD  - c Department of Functional Imaging , BC Cancer Agency , Vancouver , British
      Columbia , Canada.
AD  - d Department of Radiology , University of British Columbia , Vancouver , British 
      Columbia , Canada.
FAU - Lin, Kuo-Shyan
AU  - Lin KS
AD  - a Department of Molecular Oncology , BC Cancer Agency , Vancouver , British
      Columbia , Canada.
AD  - c Department of Functional Imaging , BC Cancer Agency , Vancouver , British
      Columbia , Canada.
AD  - d Department of Radiology , University of British Columbia , Vancouver , British 
      Columbia , Canada.
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Enzyme Inhib Med Chem
JT  - Journal of enzyme inhibition and medicinal chemistry
JID - 101150203
RN  - 0 (Carbonic Anhydrase Inhibitors)
RN  - 0 (Fluorine Radioisotopes)
RN  - EC 4.2.1.1 (Carbonic Anhydrase IX)
SB  - IM
MH  - Animals
MH  - Carbonic Anhydrase IX/*antagonists & inhibitors/metabolism
MH  - Carbonic Anhydrase Inhibitors/*analysis/chemistry/pharmacokinetics/*pharmacology
MH  - Colorectal Neoplasms/diagnosis/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - *Drug Design
MH  - Fluorine Radioisotopes
MH  - Humans
MH  - Mice
MH  - Molecular Imaging/*methods
MH  - Molecular Structure
MH  - Positron-Emission Tomography/*methods
MH  - Structure-Activity Relationship
OTO - NOTNLM
OT  - Carbonic anhydrase IX
OT  - fluorine-18
OT  - molecular imaging
OT  - positron emission tomography
EDAT- 2017/04/08 06:00
MHDA- 2017/04/21 06:00
CRDT- 2017/04/08 06:00
AID - 10.1080/14756366.2017.1308928 [doi]
PST - ppublish
SO  - J Enzyme Inhib Med Chem. 2017 Dec;32(1):722-730. doi:
      10.1080/14756366.2017.1308928.

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