azd4694 and 2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole

(11)C-Pittsburgh compound-B ((11)C-PiB) is the benchmark radiotracer for imaging of β-amyloid (Aβ) plaque in Alzheimer disease (AD). (18)F-labeled Aβ tracers subsequently developed for clinical use show higher nonspecific white matter binding and, in some cases, lower cortical binding in AD that could lead to less accurate interpretation of scans. We compared the cortical and white matter binding of a new (18)F-labeled Aβ tracer, (18)F-AZD4694 (recently renamed NAV4694), with (11)C-PiB in the same subjects.. Forty-five participants underwent PET imaging with (11)C-PiB and (18)F-AZD4694 (25 healthy elderly controls [HCs], 10 subjects with mild cognitive impairment, 7 subjects with probable AD, and 3 subjects with probable frontotemporal dementia). Images were coregistered so that region-of-interest placement was identical on both scans, and standardized uptake value ratios (SUVRs) using the cerebellar cortex as a reference region were calculated between 40 and 70 min after injection for both tracers.. (18)F-AZD4694 showed reversible binding kinetics similar to (11)C-PiB, reaching an apparent steady state at 50 min after injection. Both radiotracers showed a similar dynamic range of neocortical SUVR (1.1-3.3 and 1.0-3.2 SUVR for (11)C-PiB and (18)F-AZD4694, respectively) and identical low nonspecific white matter binding, with frontal cortex-to-white matter ratios of 0.7 ± 0.2 and 1.3 ± 0.2 for both radiotracers in HCs and AD subjects, respectively. There was an excellent linear correlation between (11)C-PiB and (18)F-AZD4694 neocortical SUVR (slope of 0.95, r = 0.99, P < 0.0001).. (18)F-AZD4694 displays imaging characteristics nearly identical to those of (11)C-PiB. The low white matter and high cortical binding in AD indicate that this tracer is well suited to both clinical and research use.

Topics: Aged; Aging; Amyloid beta-Peptides; Aniline Compounds; Benzofurans; Benzothiazoles; Brain; Dementia; Female; Humans; Hydrocarbons, Fluorinated; Male; Molecular Imaging; Positron-Emission Tomography; Thiazoles

A common quantitative output value for PET measures of β-amyloid (Aβ) binding across tracers and methods would allow better comparison of data across sites and application of universal diagnostic and prognostic values. A method has recently been developed that generates a unit of measurement called the centiloid. We applied this method to 2-[2-(18)F-fluoro-6-(methylamino)-3-pyridinyl]-1-benzofuran-5-ol ((18)F-NAV4694) and (11)C-Pittsburgh compound B ((11)C-PiB) Aβ images to derive the scaling factor required to express tracer binding in centiloids.. Fifty-five participants, including 10 young controls (33 ± 7 y old), underwent both (11)C-PiB and (18)F-NAV4694 imaging no more than 3 mo apart, with the images acquired 50-70 min after tracer injection. The images were spatially normalized and analyzed using the standard centiloid method and regions (cortex and whole-cerebellum reference) downloaded from the Global Alzheimer Association Interactive Network website.. SUV ratios (SUVRs) showed a strong correlation in tracer binding ((18)F-NAV4694 SUVR = 1.09 × (11)C-PiB SUVR - 0.08, R(2) = 0.99). The equation to convert (18)F-NAV4694 to centiloids [100 × ((18)F-NAV4694 SUVR - 1.028)/1.174] was similar to a published equation for (11)C-PiB [100 × ((11)C-PiB SUVR - 1.009)/1.067]. In the young controls, the variance ratio ((18)F-NAV4694 centiloid SD divided by (11)C-PiB centiloid SD) was 0.85.. The results for both (11)C-PiB and (18)F-NAV4694 can now be expressed in centiloids, an important step that should allow better clinical and research use of Aβ imaging. The standard centiloid method also showed that (18)F-NAV4694 has slightly higher Aβ binding and lower variance than (11)C-PiB, important properties for detecting early Aβ deposition and change over time.

Topics: Adult; Amyloid beta-Peptides; Aniline Compounds; Benzofurans; Benzothiazoles; Brain; Female; Fluorine Radioisotopes; Humans; Hydrocarbons, Fluorinated; Image Interpretation, Computer-Assisted; Male; Molecular Imaging; Positron-Emission Tomography; Practice Guidelines as Topic; Protein Interaction Mapping; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Thiazoles; Tissue Distribution

[(18)F]AZD4694 (2-(2-(18)F-fluoro-6-(methylamino)-3-pyridyl)benzofuran-5-ol) is a radioligand suitable for imaging of amyloid beta deposits in the living human brain using positron emission tomography (PET). Here, we report the preparation and pharmacokinetic profile of its carbon-11 (t1/2 = 20.4 min) labeled isotopolog [(11)C]AZD4694 and compare [(11)C]AZD4694 with the hitherto most widely applied amyloid PET radioligand [(11)C]Pittsburgh Compound B (PiB).. The immediate unlabeled precursor to [(11)C]AZD4694 was prepared in a four-step convergent synthesis. Subsequent N-(11)C-methylation of this precursor with [(11)C]methyl iodide yielded [(11)C]AZD4694, which after isolation and formulation was injected into cynomolgus monkeys. The radioactivity in nonhuman primate brain following injection of [(11)C]AZD4694 and [(11)C]PiB was measured using PET.. [(11)C]AZD4694 was prepared in a 60 % incorporation yield. In a head to head comparison with [(11)C]PiB, it appeared that [(11)C]AZD4694 displayed slightly lower nonspecific binding in white matter than [(11)C]PiB as well as more rapid pharmacokinetics in the brain.. The advantageous pharmacokinetic profile and low nonspecific binding render [(11)C]AZD4694 a promising PET radioligand for imaging of amyloid beta in the human brain with PET.

Topics: Amyloid beta-Peptides; Aniline Compounds; Animals; Benzofurans; Brain; Carbon Radioisotopes; Humans; Hydrocarbons, Fluorinated; Macaca fascicularis; Magnetic Resonance Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles; Time Factors