0000000000623666
AUTHOR
Pauline Carter
Characterisation of [11C]PR04.MZ in Papio anubis baboon: A selective high-affinity radioligand for quantitative imaging of the dopamine transporter
N-(4-fluorobut-2-yn-1-yl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane (PR04.MZ, 1) is a PET radioligand for the non-invasive exploration of the function of the cerebral dopamine transporter (DAT). A reliable automated process for routine production of the carbon-11 labelled analogue [11C]PR04.MZ ([11C]-1) has been developed using GMP compliant equipment. An adult female Papio anubis baboon was studied using a test–retest protocol with [11C]-1 in order to assess test–retest reliability, metabolism and CNS distribution profile of the tracer in non-human primates. Blood sampling was performed throughout the studies for determination of the free fraction in plasma (fP), plasma input functions and m…
Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors
Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addition to low HDAC potency and selectivity observed, poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here we report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compounds based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET im…
PET Studies of d-Methamphetamine Pharmacokinetics in Primates: Comparison with l-Methamphetamine and (—)-Cocaine
The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (-)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding.d- and l-methamphetamine and (-)-cocaine were labeled with (11)C via alkylation of the norprecursors with (11)C-methyl iodide using literature methods. Six different ba…
Reinvestigation of the synthesis and evaluation of [N-methyl-11C]vorozole, a radiotracer targeting cytochrome P450 aromatase
Abstract Introduction We reinvestigated the synthesis of [ N -methyl- 11 C]vorozole, a radiotracer for aromatase, and discovered the presence of an N -methyl isomer which was not removed in the original purification method. Herein we report the preparation and positron emission tomography (PET) studies of pure [ N -methyl- 11 C]vorozole. Methods Norvorozole was alkylated with [ 11 C]methyl iodide as previously described and also with unlabeled methyl iodide. A high-performance liquid chromatography (HPLC) method was developed to separate the regioisomers. Nuclear magnetic resonance (NMR) spectroscopy ( 13 C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign s…
Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET
The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in…