A Structure‐Activity Relationship Study of Bimodal BODIPY‐Labeled PSMA‐Targeting Bioconjugates. (24th May 2021)

• Record Type: Journal Article
• Authors: Stemler, Tobias; Hoffmann, Caroline; Hierlmeier, Ina M.; Maus, Stephan; Krause, Elmar; Ezziddin, Samer; Jung, Gregor; Bartholomä, Mark D.
• Is Part Of: ChemMedChem. Volume 16:Number 16(2021)
• Page Start: 2535
• Page End: 2545
• Publication Date: 2021-05-24
• Subjects: bimodal imaging -- PET -- BODIPY -- PSMA -- fluorescence imaging; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100210
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 19 F/ 18 F 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 18 F‐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. Abstract : 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.