MBC94, a Conjugable Ligand for Cannabinoid CB₂ Receptor Imaging

Abstract

Cannabinoid CB 2 receptor is a particularly attractive target for noninvasive imaging of neuroinflammation and monitoring of therapeutic efficacy. Its expression is low to undetectable in healthy brain and induced in resident microglial cells (the macrophage of the brain) after cerebral ischemia, injury, and in neuroinflammatory disease. Additionally, immune cells migrating across the blood-brain barrier typically express CB 2 receptors, which adds to the expression pool of this target and provides a reliable indicator of inflammation in the brain. Here, we synthesized a novel conjugable CB 2 receptor ligand, mbc94, which has a terminal amino group that allows for facile conjugation to imaging moieties. A near-infrared (NIR) dye labeled mbc94, NIRmbc94, was developed for CB 2 targeted imaging. Preliminary evidence, including in vitro fluorescence imaging and a competition study, showed that NIRmbc94 specifically labeled CB 2-expressing cells.

Targeted zwitterionic near infrared fluorescent probe for improved imaging of type 2 cannabinoid receptors

“…Briefly, we first prepared ZW-Cl and mbc94 using the previously reported methods. 18,28 Next, (e) Fig. 3 The concentration-dependent spectra of ZW760 in water.…”

“…The precursor dye ZW-Cl and the ligand mbc94 were synthesized using the previously reported procedure. 18,28 A Biotage (Charlotte, North Carolina) microwave reactor (model: Initiator þ US/JPN 356007) was employed for the synthesis of the dye ZW760. Flash column chromatography was performed on a Teledyne ISCO (Lincoln, Nebraska) (combiflash RF) purification system with silica gel (standard grade, 60A, Sorbtech, Norcross, Georgia) or C18-reversed phase silica gel (20 to 40 μm, RediSepRf).…”

“…CB 2 R expression is high only in spleen and lymph nodes, and low-or even undetectable-in brain, thyroid, retina, placenta, skeletal muscle, kidney, liver, adrenal gland, heart, prostate, and ovary. 17,18 This allows for imaging of physiological CB 2 R activity in the immune system with low background elsewhere. In certain pathological conditions, CB 2 R expression is greatly up-regulated in the diseased cells.…”

Targeted Delivery with Peptidomimetic Conjugated Self-Assembled Nanoparticles

“…In addition to coating with self-assembled macromers, MNPs are conjugated with peptidomimetic ligands for targeted imaging of a specific cell type or malignant tissue. These include ligands that target α3 integrin receptors on glioblastoma cells (85), CXCR-4 receptors on HIV infected cells and tumor cells (137), peripheral benzodiazepine receptors for imaging traumatic brain injury (138), vesicular monoamine transporter-2 for imaging pancreatic beta-cell mass (139), cannabinoid receptors for neuroinflammation imaging (140), peroxisome proliferator-activated receptor for imaging metabolic and inflammatory disease (141), Sigma receptors for prostate cancer imaging (142), translocator protein for tumor imaging (143), and serotonin transporter receptor for imaging midbrain of patients with depression (144). Inorganic NPs, coated with self-assembled macromers for stability and anti-fouling and conjugated with targetspecific ligands, are advancing imaging from the anatomybased level to the molecular level (145).…”

Synthesis of functional near infrared pyrrolopyrrole cyanine dyes for optical and photoacoustic imaging

“…These dyes have adjustable optical properties and high extinction coeffi cients, often >150 000 m /cm (Licha , 2002 ). In addition, many cyanine dyes can be easily conjugated to targeting moieties, imparting molecular specifi city or selectivity to targeted cells or tissues (Achilefu , 2004 ;Bai et al , 2008 ;Ye et al , 2008 ).…”