Fully automated synthesis and initial PET evaluation of [11C]PBR28

Abstract

Fully automated synthesis and initial PET evaluation of a TSPO radioligand, [ 11 C]PBR28 (N-(2-[ 11 C]methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide), are reported. These results facilitate the potential preclinical and clinical PET studies of [ 11 C]PBR28 in animals and humans. Keywords Translocator protein (TSPO); [ 11 C]PBR28; Radiosynthesis; Positron emission tomography (PET); Traumatic brain injury (TBI); Brain imagingTranslocator protein 18 kDa (TSPO, formerly known as the peripheral benzodiazepine receptor) 1 is a protein found in lung, liver, heart, spleen, kidney, adrenals, brain, glial cells, masts cell and macrophages, and is implicated in numerous nervous system disorders such as epilepsy, cerebral ischemia, nerve injury and neurodegenerative diseases, and immune system diseases such as cancer. 2 Brain TSPO density increases in several neuropathological conditions and after experimental injuries to the central nervous system as well. 3 TSPO is an attractive target for molecular imaging of neuroinflammation like Alzheimer's disease and tumor progression using the biomedical imaging technique positron emission tomography (PET). 4 The prototypical TSPO-selective PET radioligand is [ 11 C]PK11195; however, it is reported to have many limitations such as low brain uptake and low sensitivity. 4 (Qi-Huang Zheng).. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2010 October 1. The precursor N- (2-hydroxybenzyl)-N-(4-phenoxypyridin-3-yl) NaH was used as a strong base instead of ( t Bu) 4 NOH, and CH 3 CN was used as the reaction solvent instead of MeOH. The reaction temperature 80 °C was higher than room temperature, and the reaction time was only 3 min, shorter than 7 min in the literature. We also used a "vial" method instead of the reported "loop" method. Therefore, the radiochemical yields for [ 11 C]PBR28 in our method is much higher than that reported previously (26%). 11 The radiosynthesis was performed in an in-house automated multi-purpose 11 C-radiosynthesis module, allowing measurement of specific radioactivity during synthesis. 19,20 The overall synthesis, purification and formulation time was 25-30 min from EOB. The specific radioactivity was in a range of 5-15 Ci/μmol at EOB. Chemical purity and radiochemical purity were determined by analytical HPLC. 21 The chemical purity of the precursor and reference standard was > 96%. The radiochemical purity of the target tracer was > 99% determined by radio-HPLC through γ-ray (PIN diode) flow detector, and th...

Pharmacokinetic Analysis of 11C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-11C-PK11195

“…Tracer Synthesis 11 C-PBR28 was synthesized following a previously described procedure (17), with slight modifications. The precursor was dissolved in 300 mL of dimethyl-sulfoxide instead of acetonitrile, and 10 mg of potassium hydroxide were used as base instead of sodium hydride.…”

Influence of TSPO Genotype on 11C-PBR28 Standardized Uptake Values

“…11 C-PBR28 was synthesized as described previously (16). Dynamic PET scans (HR+; Siemens) were initiated with injection of approximately 555 MBq of 11 C-PBR28 (Table 1).…”

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

“…11,12 Like others, we have used [ 11 C]PBR28-PET (Figure 1) to image neuroinflammation, targeting the 18-kDa translocator protein (TSPO) formerly named the peripheral benzodiazepine receptor (PBR). 13,14 However, the limitations 15,16 of [ 11 C]PBR28-PET such as low receptor binding, high inter-subject variability in binding affinity, and nonspecific binding in the human brain, due to TSPO polymorphism, have motivated us to search for new molecular targets and PET radioligands.…”