[68Ga]Pentixafor: A Novel PET Tracer for Imaging CXCR4 Status in Patients with Multiple Myeloma

Chemokine receptors form a large family of G-protein coupled receptors that mediate chemotaxis of cells towards a gradient of chemokines. The C-X-C chemokine receptor-4 (CXCR4, also known as fusin, CD184) exerts its biological effects by binding its ligand CXCL12 (or Stromal-cell derived factor-1, SDF-1) which activates downstream pathways, ultimately resulting in altered cell adhesion and cell homing. Physiologically, the CXCR4/CXCL12 interaction plays a pivotal role in the recruitment and homing of hematopoietic stem/ progenitor cells (HSPC) and immune cells. In cancer, CXCR4 expression is associated with tumor dissemination and prognosis. Using multiple myeloma (MM) as an exemplary CXCR4-expressing cancer entity, we report the evaluation of [⁶⁸Ga]Pentixafor-PET as a method for in vivo mapping of CXCR4 expression density by means of Positron Emission Tomography. [⁶⁸Ga]Pentixafor-PET provides images with excellent specificity and contrast when assessed in mice xenografted with human CXCR4-positive MM. We next analyzed CXCR4 expression using [⁶⁸Ga]Pentixafor-PET in a cohort of fourteen patients with advanced MM. These patients also underwent standard [¹⁸F]Fluoro-Deoxyglucose-PET (FDG-PET). Nine of fourteen FDG-PET scans were rated visually positive, whereas ten of fourteen Pentixafor-PET scans revealed MM manifestations. Assessment of blood counts and standard CD34+ flow cytometry did not reveal significant blood count changes or alterations in HSPC frequency associated with tracer application. These data document the first methodology for clinical PET imaging of CXCR4 in a cohort of MM patients. [⁶⁸Ga]Pentixafor-PET opens a broad field of clinical investigations on CXCR4 expression and regulation in the cancer field and beyond.