Fluorine-18 labeling of three novel D-peptides by conjugation with N-succinimidyl-4-[18F]fluorobenzoate and preliminary examination by postmortem whole-hemisphere human brain autoradiography

Introductionβ-Amyloid (Aβ) plaques and neurofibrillary tangles are the main characteristics of Alzheimer's disease (AD). Positron emission tomography (PET), a high-resolution, sensitive, and noninvasive imaging technique, has been widely utilized in visualizing the localization of plaques and tangles and thereby distinguishing between AD and healthy controls. A small 12-mer d-enantiomeric peptide (amino acid sequence=QSHYRHISPAQV), denoted as D1, has high binding affinity to Aβ in vitro in the sub-micromolar range, and consequently, its radiolabeled analogues have a potential as radioligands for visualizing amyloid plaques in vivo by PET.AimThe aims of the present work were to develop three different potent D1 derivative peptides labeled with fluorine-18 and to examine them in the AD and control postmortem human brain by autoradiography (ARG).MethodsThree different D1 derivative peptides were radiolabeled with fluorine-18 ([¹⁸F]ACI-87, [¹⁸F]ACI-88, [¹⁸F]ACI-89) using the prosthetic group N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) and purified by high performance liquid chromatography (HPLC). Preliminary ARG measurements were performed in AD and control brains.ResultsThe three fluorine-18-labeled d-peptides were obtained in a total synthesis time of 140 min with radiochemical purity higher than 98%. The specific radioactivities of the three different D1 derivative peptides were between 9 and 113 GBq/μmol. ARG demonstrated a higher radioligand uptake in the cortical gray matter and the hippocampus in the AD brain as compared to age-matched control brain.ConclusionsFluorine-18 labeling of the three novel D1 derivative peptides using [¹⁸F]SFB was successfully accomplished. Higher contrast between AD and control brain slices demonstrates their potential applicability for further use in vivo by PET.     

4-[18F]fluoroglutamic acid (BAY 85-8050), a new amino acid radiotracer for PET imaging of tumors: synthesis and in vitro characterization

There is a high demand for tumor specific PET tracers in oncology imaging. Besides glucose, certain amino acids also serve as energy sources and anabolic precursors for tumors. Therefore, (18)F-labeled amino acids are interesting probes for tumor specific PET imaging. As glutamine and glutamate play a key role in the adapted intermediary metabolism of tumors, the radiosynthesis of 4-[(18)F]fluoro l-glutamic acid (BAY 85-8050) as a new specific PET tracer was established. Cell-uptake studies revealed specific tumor cell accumulation.     

An efficient one‐step radiosynthesis of [18F]FE‐PE2I,a PET radioligand for imaging of dopamine transporters

The aim of this study was to develop a direct fluorination method for the preparation of [¹⁸F]‐(E)‐N‐(3‐iodoprop‐2‐enyl)‐2β‐carbofluoroethoxy‐3β‐(4′‐methyl‐phenyl)nortropane ([¹⁸F]FE‐PE2I (VI). The synthesis procedure relies on the conventional Kryptofix‐mediated nucleophilic ¹⁸F‐substitution of the tosylate group in the precursor, TsOE‐PE2I (V). Out of reaction conditions tested, the highest fluorination efficiency was obtained in dimethyl sulfoxide at 140°C. The reaction mixture was purified by semi‐preparative HPLC, followed‐up by a standard Sep‐Pak SPE procedure. On average, 1.0 GBq of [¹⁸F]FE‐PE2I was produced from 5‐min irradiation at 35 μA (dimethyl sulfoxide, 5 min/140°C). Decay‐uncorrected yield of the product after HPLC purification and formulation was in the order of 20%. Specific radioactivity of [¹⁸F]FE‐PE2I at 15 min after EOS was 3.3–5.1 Ci/µmol (n = 3); radiochemical purity was >98% (n = 4). This direct nucleophilic fluorination strategy is well suited for the automation of the entire synthesis of [¹⁸F]FE‐PE2I in a modern PET synthesizer for human PET application. In addition, the ¹⁸F‐incorporation rate into TsOE‐PE2I was evaluated using radio‐thin layer chromatography (TLC) and radio‐HPLC. The suggested HPLC method (ACE 5 C18‐HL column and acetonitrile/0.1 M NH₄CO₂ (80:20)) was found to be suitable for evaluation of ‘free’ ¹⁸F‐fluoride in the reaction mixture; in addition, this method allowed the detection of three radiolabelled by‐products that were not discernable with the TLC approach. Therefore, we conclude that the HPLC approach may serve as a good alternative to traditional radio‐TLC technique as it provides more detailed information about the fluorination process in the reaction kinetics or optimization studies. Copyright © 2012 John Wiley & Sons, Ltd.