Imaging CXCR4 Expression with Iodinated and Brominated Cyclam Derivatives
- PDF / 788,548 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 18 Downloads / 193 Views
RESEARCH ARTICLE
Imaging CXCR4 Expression with Iodinated and Brominated Cyclam Derivatives Hanwen Zhang,1 Masatomo Maeda,2,3 Masahiro Shindo,2,3 Myat Ko,2 Mayuresh Mane,2 Christian Grommes,2 Wolfgang Weber,1,4 Ronald Blasberg 1,2,5 1
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Department of Neurosurgery, Nozaki Tokushukai Hospital, Osaka, Japan 4 Department of Nuclear Medicine, Technical University Munich, Munich, Germany 5 Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, Zuckerman Research Center (ZRC), Z-2060, 1275 York Avenue, New York, NY, 10065, USA 2
Abstract Purpose: CXCR4 is one of several “chemokine” receptors expressed on malignant tumors (including GBM and PCNSL) and hematopoietic stem cells. Although 68Ga-pentixafor and 68GaNOTA-NFB have been shown to effectively image CXCR4 expression in myeloma and other systemic malignancies, imaging CXCR4 expression in brain tumors has been more limited due to the blood-brain barrier (BBB) and a considerable fraction of CXCR4 staining is intracellular. Methods: We synthesized 6 iodinated and brominated cyclam derivatives with high affinity (low nM range) for CXCR4, since structure-based estimates of lipophilicity suggested rapid transfer across the BBB and tumor cell membranes. Results: We tested 3 iodinated and 3 brominated cyclam derivatives in several CXCR4(+) and CXCR4(−) cell lines, with and without cold ligand blocking. To validate these novel radiolabeled cyclam derivatives for diagnostic CXCR4 imaging efficacy in brain tumors, we established appropriated murine models of intracranial GBM and PCNSL. Based on initial studies, 131IHZ262 and 76Br-HZ270-1 were shown to be the most avidly accumulated radioligands. 76BrHZ270-1 was selected for further study in the U87-CXCR4 and PCNSL #15 intracranial tumor models, because of its high uptake (9.5 ± 1.3 %ID/g, SD) and low non-specific uptake (1.6 ±
Hanwen Zhang and Masatomo Maeda contributed equally to this work. Key Points • New derivatives of AMD3100 and AMD3465, based on radiohalogenating the phenyl moiety directly, were successfully designed and synthesized with greater than 98% purity. • Selected halogenated cyclam derivatives successfully imaged CXCR4expressing subcutaneous tumors, but not intracranial tumors. • The halogenated cyclam analogues were expected to be hydrophobic, as suggested by structure-based estimates of their lipophilicity, but the estimates were significantly different from the “measured” octanol/PBS partition coefficient (LogD) of the synthesized radioligands. • Due to a comparatively intact blood-tumor barrier in the experimental animal models, intracranial CXCR4 expressing gliomas and PCNSL were not well visualized. Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-020-01480-1) contains supplementary material, which is available to authorized users. Correspondence to: Ronald Bla
Data Loading...
