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Introduction In this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. Methods p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [ 18 F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(−) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent. Results The crystallographic data showed interaction of the p -fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [ 18 F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(−) cells (0.08%) at 4h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4h. Conclusions We have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [ 18 F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. Advances in Knowledge The only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [ 18 F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials. Implications for Patient Care Our preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.

The binding of three tracers for monoaminergic terminals was mapped in the brain of healthy young (N=6) and healthy old rhesus monkeys (N=4), aged monkeys with mild unilateral intracarotid MPTP lesions (N=3), and monkeys of intermediate age with severe systemic MPTP lesions (N=6). The ligand for monoaminergic vesicles (+)-[(11)C]dihydrotetrabenazine (+DTBZ) had a mean binding potential (pB) of 1.4 in striatum of the healthy young monkeys, which was reduced by 20% in putamen of the old monkeys. The catecholamine transporter ligand (+)-[(11)C]methylphenidate (+MP) had a mean pB of 1.3 in striatum of the young monkeys, which was reduced by 40% in caudate and putamen of the old monkeys. The DOPA decarboxylase substrate [(18)F]fluoro-l-DOPA (FDOPA) had a mean decarboxylation coefficient (k(3)(S)) of 0.4 h(-1) in striatum of the young group, and was not significantly reduced in the aged group. Of the three ligands, only +DTBZ pB was significantly reduced in striatum of the small group of animals with mild unilateral lesions. In the group with systemic MPTP lesions, the mean reduction of the binding of the three ligands was 80% in the caudate and putamen. However, the decline in +MP pB in the ventral striatum (-75%) exceeded the declines of +DTBZ pB and FDOPA k(3)(S) in that region (-65%), suggesting that compensatory down-modulation of uptake sites may occur in the striatal regions with the least dopamine depletion. Binding of all three ligands was reduced by 50% in the anterior cingulate cortex and in the thalamus, suggesting toxicity of MPTP for extrastriatal catecholamine innervations. +DTBZ binding in the hypothalamus, presumably mainly in serotonin fibers, was unaffected by systemic MPTP treatment. Of the three tracers, +DTBZ was most sensitive for detecting MPTP-induced dopamine depletion in monkey striatum.

A new thin window support system for the accelerator production of positron emitters (e.g. 17 F, 18 F 11 C, 15 O) has been developed. The integrated support grid and cooling design has been optimized for 6–13 MeV protons or deuterons. The water-cooled support grid regularly operated at >100 μA of 6 MeV deuterons and protons. The grid performed without failure at ⩾50 μA of 13 MeV protons on a 3.1 MPa gas target using 25.4 μm aluminum target foil. Transmission for the smallest hole grid of 72% based on uniform parallel beam agreed with the measured yield of 71±1% compared to the theoretical maximum yield.

The synthesis of [18F]FDG using tetrabutylammonium bicarbonate has been successfully modified to accommodate automation using the Optomux® control system. Noteworthy changes to the methods previously reported are the addition of a small ion exchange column which serves to quantitatively trap [18F]fluoride from the target water and the extensive use of thermocouple and radiation detector feedback for process control. The radiochemical yields observed over 30 runs are: 50.3 ± 9% decay corrected and 34.6 ± 6% decay uncorrected.

A convenient three-step synthesis of the title compound from commercially available 3,4-dimethoxyphenethylamine is described. The title compound is a stable, crystalline, organic-soluble solid which reacts with carrier-added [18F]acetyl hypofluorite to yield 6-[18F]fluorodopamine (20 ± 7% radiochemical yield EOS, n = 3) following deprotection with hydriodic acid.

Elemental fluorine and acetyl hypofluorite, labeled with 18 F, were added to eight simple aryl-tin derivatives. Both reagents gave good radiochemical yields of labeled aryl fluorides. Overall, acetyl hypofluorite gave more consistent yields (∼70%), while F 2 gave more variable yields (54% – 95%).

This work describes the synthesis and purification of l -6-[18F]fluorodopa synthesized via the reaction of acetyl hypofluorite with a mercury-dopa derivative. The mercurated starting material and the mercury compounds produced in the reaction are efficiently removed by passage of the reaction mixture through a mercaptan modified silica gel. After evaporation the residue was treated with HI, and purified by HPLC to give the pure product in 12% radiochemical yield (decay corrected) and containing

Twelve derivatized dihydroxyphenylalanine (dopa) substrates were treated with gaseous [18F]acetyl hypofluorite. Radiochemical yields of [18F]6-fluorodopa, obtained after HI hydrolysis, ranged from < 1–8% (decay corrected). The highest yield was obtained using l-methyl-N-acetyl-[β-(3-methoxy-4-acetoxyphenyl]alaninate.

The synthesis of 2-deoxy-2[18F]fluoro-D-glucose has been simplified by the use of C-18 SEP PAK cartridges. The fluorinated sugar produced from the reaction of acetyl hypofluorite and tri-acetyl glucal (TAG) was extracted from the neutralized reaction mixture with C-18 SEP PAK cartridges. The product was washed off the cartridge with diethyl ether and hydrolyzed by HCl. After hydrolysis the product was purified by passage through ion retardation resin, alumina and another C-18 cartridge. The radiochemical purity was 98% and the radiochemical yield was 28%, decay corrected to EOB, with a total synthesis time of 50 min from EOB.

This paper describes the separation of lipophilic amine radiopharmaceuticals on normal phase silica using a reversed phase type eluant. This class of compound usually gives very poor peak symmetry on reversed phase columns. However, excellent separation of a number of amines of interest to Positron Emission Tomography, such as spiperone and its derivatives, has been achieved on this system.