Carbon-11 labeled indolylpropylamine analog as a new potential PET agent for imaging of the serotonin transporter.

The synthesis and structure-activity relationship of a new class of indole derivatives with low-nanomolar affinity for the SERT and high selectivity versus the 5-HT1A receptor were recently reported. Based on their chemical structure, four new indolylpropylamine derivatives which contain atoms to afford future labeling with PET isotopes, were synthesized and evaluated as SERT ligands. The chemistry of these novel derivatives, their biological evaluation, the general method of preparing the precursor indole for labeling, and the C-11 labeling of the most promising indole derivative, are described herein.

Formation of fluorine-18 labeled diaryl ureas--labeled VEGFR-2/PDGFR dual inhibitors as molecular imaging agents for angiogenesis.

Urea subunits are common components of various pharmaceuticals' core structure. Since in most cases the design and development of PET biomarkers is based on approved or potential drugs, there is a growing need for a general labeling methodology of urea-containing pharmacophores. As a part of research in the field of molecular imaging of angiogenic processes, we synthesized several highly potent VEGFR-2/PDGFR dual inhibitors as potential PET biomarkers. The structure of these inhibitors is based on the N-phenyl-N'-{4-(4-quinolyloxy)phenyl}urea skeleton. A representative inhibitor was successfully labeled with fluorine-18 by a three-step process. Initially, a two-step radiosynthesis of 4-[(18)F]fluoro-aniline from 1,4-dinitrobenzene (60min, EOB decay corrected yield: 63%) was performed. At the third and final step, the 4-[(18)F]fluoro-aniline synthon reacted for 30min at room temperature with 4-(2-fluoro-4-isocyanato-phenoxy)-6,7-dimethoxy-quinoline to give complete conversion of the labeled synthon to 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-[(18)F]fluoro-phenyl)-urea. The desired labeled product was obtained after total radiosynthesis time of 3h including HPLC purification with 46+/-1% EOB decay corrected radiochemical yield, 99% radiochemical purity, 99% chemical purity, and a specific activity of 400+/-37GBq/mmol (n=5).

Improved method for the quality assurance of [C-11]choline.

[C-11]choline is a very promising radiomarker for the diagnosis of various human tumors using Positron Emission Tomography (PET). The existing quality control process for [C-11]choline is complicated and combines two HPLC methods with limited separation and sensitivity which prevent the accurate determination of the specific activity. We have developed a new efficient single HPLC method for the detection of choline chloride and dimethylaminoethanol with high resolution and sensitivity using cation-exchange chromatography.

Cerebral activation associated with sexual arousal in response to a pornographic clip: A 15O-H2O PET study in heterosexual men.

This study attempted to use PET and 15O-H2O to measure changes in regional cerebral blood flow (rCBF) during sexual arousal evoked in 10 young heterosexual males while they watched a pornographic video clip, featuring heterosexual intercourse. This condition was compared with other mental setups evoked by noisy, nature, and talkshow audiovisual clips. Immediately after each clip, the participants answered three questions pertaining to what extent they thought about sex, felt aroused, and sensed an erection. They scored their answers using a 1 to 10 scale. SPM was used for data analysis. Sexual arousal was mainly associated with activation of bilateral, predominantly right, inferoposterior extrastriate cortices, of the right inferolateral prefrontal cortex and of the midbrain. The significance of those findings is discussed in the light of current theories concerning selective attention, "mind reading" and mirroring, reinforcement of pleasurable stimuli, and penile erection.

Potential (18)F-labeled biomarkers for epidermal growth factor receptor tyrosine kinase.

As PET candidate tracers for EGFr-TK, five 4-(anilino)quinazoline derivatives, each fluorinated in the aniline moiety, were prepared. Each was tested in vitro for inhibition of EGFr autophosphorylation in A431 cell line. The leading compounds were then radiolabeled with (18)F and cell binding experiments, biodistribution and PET studies in A431 tumor-bearing mice were performed. Metabolic studies were carried out in a mice control group. From our results, we concluded that while in vitro experiments indicates efficacy of 4-(anilino)quinazoline compounds, kinetic factors and rapid blood clearance make them unsuitable as tracers for nuclear medicine imaging of EGFr-TK.

Application of a novel phenylpiperazine formation reaction to the radiosynthesis of a model fluorine-18-labeled radiopharmaceutical (18FTFMPP).

The labeled serotonin agonist 3-[18F]fluoro-N-(alpha,alpha,alpha-trifluoro-m-tolyl)piperazine (18FTFMPP) was prepared rapidly using the labeling procedure for trifluorotoluenes, [18F]fluoro-for-nitro exchange, followed by an alumina-supported bis-alkylation. After normal-phase HPLC purification, the labeled product was obtained in 20-32% (n = 20) decay-corrected radiochemical yield with a radiochemical purity > 98% and a specific activity of 100 GBq/mumol. The synthesis time including purification was 3 h. The receptor binding affinity of FTFMPP to rat brain membranes was found to be similar to that of the nonfluorinated parent compound (TFMPP). Although TFMPP has been proposed by others as an agent for the imaging of serotonin receptors, only minimal receptor-mediated uptake was observed.