Background

[PubMed]

Alzheimer's disease (AD) is a form of dementia with a gradual memory loss and a progressive decline in mental functions overtime (1, 2). It is characterized pathologically by neuronal loss, extracellular senile plaques (aggregates of amyloid-beta peptides consisting of 40 to 42 amino acids) and intracellular neurofibrillary tangles (filaments of microtubule-binding hyper-phosphorylated protein tau) in the brain, especially in the hippocampus and associative regions of the cortex (3, 4). β-amyloid peptides and tau protein are implicated as the main causes of neuronal degeneration and cell death (5, 6).

Early diagnosis of AD is important for treatment consideration and disease management (7). Various β-amyloid imaging agents have been developed for magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET) (8-13). The binding of different derivatives of Congo red, thioflavin, stibene, and aminonaphthalene has been studied in human post-mortem brain tissue and in transgenic mice. Out of these analogues, 2-(1-(6-[(2-[¹⁸F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malono nitrile ([¹⁸F]FDDNP) was studied in humans, showing more binding in the brains of patients with AD than in those of healthy people (14). However, [¹⁸F]FDDNP showed low signal-to-noise ratios for PET imaging, because it is highly lipophilic. N-methyl-[¹¹C]-2-(4’-methylaminophenyl)-6-hydroxybenzothiasole, a β-amyloid binding compound based on a series of neutral thioflavin-T derivatives (15), was radiolabeled with the positron-emitting radionuclide ¹¹C ([¹¹C]6-OH-BTA-1 or [¹¹C]PIB). [¹¹C]6-OH-BTA-1 was found to be a promising imaging agent for the senile plaques in the brain (16). Zhang et al. (17) reported the development of a series of fluorinated polyethylene glycol (PEG) units (n = 2-5) for PET imaging of β-amyloid plaques in the brain. One of them, Trans-4-(N-methylamino)-4´-{2-[2-(2-[¹⁸F]fluoro-ethoxy)-ethoxy]-ethoxy}-stilbene ([¹⁸F]BAY94-9172), has been tested in humans.

Synthesis

[PubMed]

[¹⁸F]BAY94-9172 was readily synthesized by standard ¹⁸F-fluorination of N-BOC-protected mesylate derivative with ([¹⁸F]KF/Kryptofix 2.2.2), followed by hydrolysis (17). The radiochemical yield was 30% (decay-corrected) at the end of synthesis, and the specific activity was 48.1-55.5 GBq/μmol (1.3 -1.5 Ci/μmol) at the end of synthesis. Radiochemical purity was >99% as determined with high-performance liquid chromatography. Total synthesis time was ~ 90 min. [¹⁸F]BAY94-9172 exhibited a Log P value of 2.41.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

BAY94-9172 has a binding affinity (K_i) of 6.7 ± 0.3 nM for aggregated amyloid-beta fibrils (postmortem AD brain homogenates) in competition with [¹²⁵I]IMPY (17). The K_i Value for PIB was found to be 2.8 ± 0.5 nM. [¹⁸F]BAY94-9172 bound to the cortex of postmortem AD brain slices as visualized by autoradiography studies.

Animal Studies

Human Studies

[PubMed]

Rowe et al. (18) studied 15 patients with mild AD, 15 healthy elderly controls, and five patients with frontotemporal lobar degeneration (FTLD) with [¹⁸F]BAY94-9172 PET imaging. [¹⁸F]BAY94-9172 binding was quantified by use of the standardized uptake value ratio (SUVR), which was calculated for the neocortex with the cerebellum as reference region. Widespread neocortical binding was observed in all AD patients., Higher neocortical SUVR was observed in AD patients (2.0 ± 0.3) than in healthy controls (1.3 ± 0.2; P<0.0001) or FTLD patients (1.2 ± 0.2; P=0.009) at 90-120 min after injection with visual interpretation was 100% sensitive and 90% specific for detection of AD.

O’Keefe et al. (19) performed attenuation-corrected whole-body scans at 0, 15, 30, 45, and 60 min after injection of 350 ± 28 MBq of [¹¹C]PIB in 6 healthy subjects and at 0, 20, 60, 120, and 180 min after injection of 319 ± 27 MBq of [¹⁸F]BAY94-9172 in 3 healthy subjects. For [¹¹C]PIB, the highest absorbed doses were in the gallbladder wall (44.80 ± 29.30 µGy/MBq), urinary bladder wall (26.30 ± 8.50 µGy/MBq), liver (19.88 ± 3.58 µGy/MBq), and kidneys (12.92 ± 3.37 µGy/MBq). The effective dose (ED) was 5.29 ± 0.66 µSv/MBq. For [¹⁸F]BAY94-9172, the highest doses were also in the gallbladder wall (132.40 ± 43.40 µGy/MBq), urinary bladder wall (24.77 ± 7.36 µGy/MBq), and liver (39.07 ± 8.31 µGy/MBq). The ED was 14.67 ± 1.39 µSv/MBq. The estimated organ doses for [¹¹C]PIB were comparable to those reported in earlier research. With the doses used in published studies (300-700 MBq), the EDs would range from 1.6 to 3.7 mSv. The ED of [¹⁸F]BAY94-9172 was 30% lower than that of (18)F-FDG and, at the published dose of 300 MBq, would yield an ED of 4.4 mSv.

NIH Support

AG022559

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