Novel Peptide-Based PET Probe for Non-invasive Imaging of C-X-C Chemokine Receptor Type 4 (CXCR4) in Tumors

Abstract

The recently reported CXCR4 antagonist <b>3</b> (Ac-Arg-Ala-[DCys-Arg-2Nal-His-Pen]-CO₂H) was investigated as a molecular scaffold for a CXCR4-targeted positron emission tomography (PET) tracer. Toward this end, <b>3</b> was functionalized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononanetriacetic acid (NOTA). On the basis of convincing affinity data, both tracers, [⁶⁸Ga]NOTA analogue ([⁶⁸Ga]-<b>5</b>) and [⁶⁸Ga]DOTA analogue ([⁶⁸Ga]-<b>4</b>), were evaluated for PET imaging in "<i>in vivo</i>" models of CHO-hCXCR4 and Daudi lymphoma cells. PET imaging and biodistribution studies revealed higher CXCR4-specific tumor uptake and high tumor/background ratios for the [⁶⁸Ga]NOTA analogue ([⁶⁸Ga]-<b>5</b>) than for the [⁶⁸Ga]DOTA analogue ([⁶⁸Ga]-<b>4</b>) in both <i>in vivo</i> models. Moreover, [⁶⁸Ga]-<b>4</b> and [⁶⁸Ga]-<b>5</b> displayed rapid clearance and very low levels of accumulation in all nontarget tissues but the kidney. Although the high tumor/background ratios observed in the mouse xenograft model could partially derive from the hCXCR4 selectivity of [⁶⁸Ga]-<b>5</b>, our results encourage its translation into a clinical context as a novel peptide-based tracer for imaging of CXCR4-overexpressing tumors.