A Structure‐Activity Relationship Study of Bimodal BODIPY‐Labeled PSMA‐Targeting Bioconjugates

Autor: Caroline Hoffmann, Gregor Jung, Elmar Krause, Mark Bartholomae, Ina Hierlmeier, Stephan Maus, Tobias Stemler, Samer Ezziddin
Rok vydání: 2021
Předmět:
Glutamate Carboxypeptidase II
Male
Cancer Research
Fluorescence-lifetime imaging microscopy
Peptidomimetic
urologic and male genital diseases
01 natural sciences
Biochemistry
Cell membrane
chemistry.chemical_compound
Drug Discovery
Fluorescence microscope
General Pharmacology
Toxicology and Pharmaceutics
Internalization
media_common
Molecular Structure
Full Paper
Full Papers
medicine.anatomical_structure
Antigens
Surface
Molecular Medicine
BODIPY
Boron Compounds
media_common.quotation_subject
bimodal imaging
Structure-Activity Relationship
fluorescence imaging
Very Important Paper
LNCaP
PSMA
medicine
Humans
Structure–activity relationship
Radiology
Nuclear Medicine and imaging
Pharmacology
Dose-Response Relationship
Drug
010405 organic chemistry
Organic Chemistry
Prostatic Neoplasms
0104 chemical sciences
010404 medicinal & biomolecular chemistry
PET
Microscopy
Fluorescence
chemistry
Positron-Emission Tomography
Biophysics
Peptidomimetics
Conjugate
Zdroj: Chemmedchem
ISSN: 1860-7187
1860-7179
Popis: The aim of this study was to identify a high‐affinity BODIPY peptidomimetic that targets the prostate‐specific membrane antigen (PSMA) as a potential bimodal imaging probe for prostate cancer. For the structure‐activity study, several BODIPY (difluoroboron dipyrromethene) derivatives with varying spacers between the BODIPY dye and the PSMA Glu‐CO‐Lys binding motif were prepared. Corresponding affinities were determined by competitive binding assays in PSMA‐positive LNCaP cells. One compound was identified with comparable affinity (IC50=21.5±0.1 nM) to Glu‐CO‐Lys‐Ahx‐HBED‐CC (PSMA‐11) (IC50=18.4±0.2 nM). Radiolabeling was achieved by Lewis‐acid‐mediated 19F/18F exchange in moderate molar activities (∼0.7 MBq nmol−1) and high radiochemical purities (>99 %) with mean radiochemical yields of 20–30 %. Cell internalization of the 18F‐labeled high‐affinity conjugate was demonstrated in LNCaP cells showing gradual increasing PSMA‐mediated internalization over time. By fluorescence microscopy, localization of the high‐affinity BODIPY‐PSMA conjugate was found in the cell membrane at early time points and also in subcellular compartments at later time points. In summary, a high‐affinity BODIPY‐PSMA conjugate has been identified as a suitable candidate for the development of PSMA‐specific dual‐imaging agents.
Have it both ways: By structure–activity relationship studies, a bimodal imaging probe combining fluorescence with nuclear imaging based on BODIPY dyes with high affinity for the prostate‐specific membrane antigen (PSMA) has been identified. The bimodal conjugate demonstrated PSMA‐specific uptake in prostate cancer cells with accumulation in the cell membrane at early time points and additional accumulation in subcellular compartments at later time points.
Databáze: OpenAIRE
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