Selection and Radiolabeling of Bicyclam Analogues for Imaging CXCR4 Expression in Gliomas (GBM) and primary CNS lymphoma (PCNSL)

Background: CXCR4 is one of several chemokine receptors expressed on many malignant tumors (including GBM and PCNSL) and hematopoietic stem cells (1). Although a 68Ga labeled pentapeptide (2) has been shown to effectively image CXCR4 expression in myeloma (3), and other systemic malignancies (4), imaging CXCR4 expression in brain tumors with ⁶⁸Ga pentixaforand ⁶⁸Ga NOTA NFB (5,6) has been more limited. There are at least two potential explanations for this limitation: i) the blood brain barrier (BBB) may restrict access of radiolabeled peptides to many CXCR4 expressing tumor cells) a considerable fraction of CXCR4 staining is intracellular and intracellular CXCR4 may not be accessible to the peptides. Methods and Results: We developed iodinated and brominated bicyclam derivatives with high affinity (low nM range) for CXCR4, and had structure based LogP estimates suggesting rapid transfer across the BBB and tumor cell membranes. To test and validate these novel radiolabeled bicyclam derivatives for diagnostic CXCR4 imaging efficacy in brain tumors, we established appropriated murine models of intracranial PCNSL and GBM. Initial studies were performed testing 3 iodinated derivatives and 3 brominated derivatives in several CXCR4(+) and CXCR4(-) cell lines, with and without cold ligand blocking. Similar CXCR4(+) and CXCR4(-) s.c. tumor uptake studies were also performed, and ¹³¹I HZ262 and ⁷⁶Br HZ270 1 were shown to be most avidly accumulated radioligands in these assays. 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 nonspecific uptake (1.6±0.7 %ID/g, SD) and greater lipophilicity. However, imaging CXCR4 expression in intracranial U87 CXCR4 and PCNSL 15 tumors with ⁷⁶Br HZ270 1 was unsuccessful, following either intravenous or spinal CSF injection.

Conclusions: The absence of CXCR4 tumor imaging in the two brain tumor models with ⁷⁶Br HZ270 1 is largely due to the hydrophilicity of the radiolabeled bicyclam analogues (based on the measured octanol/water partition coefficient, LogP), in contrast to the structure based estimate of LogP and to the presence of an intact BBB and BTB in the animal intracranial tumor models.