Imaging CXCR4 Expression with Iodinated and Brominated Cyclam Derivatives

Hanwen Zhang,Ronald Blasberg,Wolfgang Weber,Masatomo Maeda,Mayuresh Mane,Myat Ko,Masahiro Shindo,Christian Grommes

doi:10.1007/s11307-020-01480-1

Abstract

PurposeCXCR4 is one of several “chemokine” receptors expressed on malignant tumors (including GBM and PCNSL) and hematopoietic stem cells. Although 68Ga-pentixafor and 68Ga-NOTA-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.MethodsWe 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.ResultsWe 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, 131I-HZ262 and 76Br-HZ270-1 were shown to be the most avidly accumulated radioligands. 76Br-HZ270-1 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 ± 0.7 %ID/g, SD) in the s.c. U87-CXCR4 tumor models. However, imaging CXCR4 expression in intracranial U87-CXCR4 and PCNSL #15 tumors with 76Br-HZ270-1 was unsuccessful, following either i.v. or spinal-CSF injection.ConclusionsImaging CXCR4 expression with halogenated cyclam derivatives was successful in s.c. located tumors, but not in CNS located tumors. This was largely due to the following: (i) the hydrophilicity of the radiolabeled analogues—as reflected in the “measured” radiotracer distribution (LogD) in octanol/PBS—which stands in contrast to the structure-based estimate of LogP, which was the rationale for initiating the study and (ii) the presence of a modest BTB in intracranial U87-CXCR4 gliomas and an intact BBB/BTB in the intracranial PCNSL animal model.

Highlights

CXC receptor 4 (CXCR4) is a cell surface transmembrane G protein receptor; it is one of several “chemokine” receptors expressed on malignant tumors and on hematopoietic stem cells [1]
Imaging CXCR4 expression with halogenated cyclam derivatives was successful in s.c. located tumors, but not in CNS located tumors. This was largely due to the following: (i) the hydrophilicity of the radiolabeled analogues—as reflected in the “measured” radiotracer distribution (LogD) in octanol/PBS—which stands in contrast to the structure-based estimate of LogP, which was the rationale for initiating the study and (ii) the presence of a modest blood-tumor barrier (BTB) in intracranial U87-CXCR4 gliomas and an intact blood-brain barrier (BBB)/BTB in the intracranial PCNSL animal model
CXCR4 is highly expressed on aggressive/ malignant tumor cells and plays a critical role in the homing of cancer cells to distant sites following binding to its ligand CXCL12

Summary

Introduction

CXCR4 is a cell surface transmembrane G protein receptor; it is one of several “chemokine” receptors expressed on malignant tumors (including glioblastoma-GBM and primary CNS lymphoma-PCNSL) and on hematopoietic stem cells [1]. CXCR4 is highly expressed on aggressive/ malignant tumor cells and plays a critical role in the homing of cancer cells to distant sites following binding to its ligand CXCL12. The chemokine CXCL12 (stromal cell-derived factor-1 (SDF-1)) binds primarily to CXC receptor 4 (CXCR4), establishing CXCL12–CXCR4 signaling pathway and are involved in the cross-talk between cancer cells, stromal cells, T cells, and their microenvironment, including the regulation and direction of T cell migration (chemotaxis), proliferation, and differentiation of immature progenitor-stem cells [2]. In PCNSL, there is little or no literature describing the association of high CXCR4 expression and prognosis

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Discussion

Conclusion