Reply: Advantages and Limits of Targeted Radionuclide Therapy with Somatostatin Antagonists.

Abstract

547 Objectives: To develop and characterize a PET radiotracer to image the macrophage colony stimulating factor 1 receptor (CSF1R). CSF-1R is a cell surface protein that belongs to a subfamily of the tyrosine kinase receptors. In the CNS, the CSF-1R is expressed by microglia the survival of which is dependent on CSF pathway. Stable expression of CSF-1R accompanies normal brain function. Altered levels of CSF-1R is associated with neuroinflammation in AD, MS, cancer and HIV.PET imaging would provide an opportunity to study the role of CSF-1R in these disorders. Methods: CSF-1R inhibitor (IC50 ~ 1 nM) 1-[11C]methyl-piperazinyl derivative [11C]JHU11744 was radiolabeled via a nor-methyl-precursor. Regional brain distribution of [11C]JHU11744 was measured in control C57/BL6mice, two mouse models of neuroinflammation (IP and intracranial LPS), and a mouse model of AD (18 mo-old TetOffAPPsi x CaMKIIα). In vivo blocking study was performed in the intracranial LPS model by administration of JHU11744followed by IV injection of [11C]JHU11744. Results: [11C]JHU11744 was prepared with a radiochemical yield of ~30%, specific radioactivity of 333-562 GBq/µmol (9,000-15,200 mCi/μmol), and a radiochemical purity of 97%. The time-activity curves showed the radioactivity peak of 6.5% ID/g tissue in all regions at 5-10 min followed by rapid washout. Comparison of regional brain uptake of [11C]JHU11744 in control and LPS-treated and AD mice demonstrated a significant increase of radioactivity in the LPS (68-114%) and AD (31%) mice. Brain uptake of [11C]JHU11744 in the intracranial LPS mice was significantly reduced (61%) in the self-blocking experiments. Conclusions: [11C]JHU11744, a potent radiolabeled CSF1R inhibitor, readily enters the mouse brain and specifically radiolabels CSF1R in the LPS model of neuroinflammation. In the AD mice the brain uptake of [11C]JHU11744 is significantly greater than in age-matched controls. [11C]JHU11744 may be a new valuable tool for studying CSF1R in neuroinflammation and neurodegeneration.