Christopher J. R. Fookes

Synthesis and biological evaluation of substituted [18F]imidazo[1,2-a]pyridines and [18F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography.

The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo[1,2- a]pyridin-3-yl)- N, N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo[1,5- a]pyrimidin-3-yl)- N, N-diethylacetamides 15 (PBR099) and 18 (PBR146) were synthesized and found to have high in vitro affinity and selectivity for the peripheral benzodiazepine receptors (PBRs) when compared with the central benzodiazepine receptors (CBRs). The corresponding radiolabeled compounds [ (18)F] 8 [ (18)F] 12, [ (18)F] 15, and [ (18)F] 18 were prepared from their p-toluenesulfonyl precursors in 50-85% radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR compounds paralleled the known localization of PBRs. In the olfactory bulbs, where the uptake of radioactivity was higher than in the rest of the brain, PK11195 and Ro 5-4864 were able to significantly inhibit [ (18)F] 12, while little or no pharmacological action of these established PBR drugs were observed on the uptake of [ (18)F] 8, [ (18)F] 15, and [ (18)F] 18 compared to control animals. Hence, [ (18)F] 12 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.

Radiosynthesis and Biological Evaluation of l- and d-S-(3-[18F]Fluoropropyl)homocysteine for Tumor Imaging Using Positron Emission Tomography

Interest in radiolabeled amino acids for metabolic imaging of cancer and limitations with [(11)C]methionine has prompted the development of a new (18)F-labeled methionine derivative S-(3-[(18)F]fluoropropyl)homocysteine ([(18)F]FPHCys). The L and D enantiomers of [(18)F]FPHCys were prepared from their respective protected S-(3-tosyloxypropyl)homocysteine precursors 1 by [(18)F]fluoride substitution using K(2.2.2) and potassium oxalate, followed by acid hydrolysis on a Tracerlab FX(FN) synthesis module. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys were isolated in 20 ± 5% radiochemical yield and >98% radiochemical and enantiomeric purity in 65 min. Competitive uptake studies in A375 and HT29 tumor cells suggest that L- and D-[(18)F]FPHCys are taken up by the L-transporter system. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys displayed good stability In Vivo without incorporation into protein at least 2 h postinjection. Biodistribution studies demonstrate good uptake in A375 tumor-bearing rodents with tumor to blood ratios of 3.5 and 5.0 for [(18)F]-L-FPHCys and [(18)F]-D-FPHCys, respectively, at 2 h postinjection.

Biosynthesis of porphyries and related macrocycles. Part 17. Chemical and enzymic transformation of isomeric aminomethylbilanes into uroporphyrinogens: proof that unrearranged bilane is the preferred enzymic substrate and detection of a transient intermediate

Six isomeric aminomethylbilanes have been built by unambiguous synthesis. One bilane has the unrearranged structure corresponding to straightforward head-to-tail assembly of four units of porphobilinogen; the other five bilanes have one or more of the pyrrole rings reversed relative to the unrearranged bilane. The action of deaminasecosynthetase on these bilanes has been studied and the results showed that (a) the enzyme system ring closes the unrearranged bilane far more efficiently than it closes any of the five isomeric bilanes, (b) under the best conditions the product formed enzymically from the unrearranged bilane is almost pure uroporphyrinogen-III, and (c) a transient intermediate is formed enzymically from the unrearranged bilane which can be detected kinetically. Further support is thereby given to the earlier conclusion that the intramolecular rearrangement which produces the natural type-III porphyries occurs at the unrearranged tetrapyrrole level.The enzymic results for the other bilanes are also described together with an improved method for analytical separation of the four isomeric esters of coproporphyrin.

Stereochemistry of formation of methyl and ethyl groups in bacteriochlorophyll a

δ-Aminolaevulinic acid has been synthesised carrying 2H and 3H isotopes at C-2 in the S-configuration; this has been incorporated by Rhodopseudomonas spheroides into bacteriochlorophyll a, degradation of which has established the mode of addition of hydrogen to the precursor vinyl group to form the ring-B ethyl group and that the decarboxylation to form the ring-B methyl group occurs with retention.

A new class of fluorinated 5-pyrrolidinylsulfonyl isatin caspase inhibitors for PET imaging of apoptosis

Thirteen compounds in a new class of fluorinated 5-pyrrolidinylsulfonyl isatin derivatives were synthesised that have potent and selective inhibitory activity against effector caspases-3 and -7. With in vivo animal PET imaging studies of cerebral ischemia being planned, N-benzylation with selected para-substituted benzylic halides allowed systematic variation of lipophilicity (logP 1.94–3.31) without decreasing inhibition potency (IC50). From this series the p-methoxybenzyl analogue was selected for initial ‘proof-of-concept’ [18F]-fluoride radiolabelling which proceeded in good yield and purity with no need for a protection/deprotection strategy.

Biosynthesis of type-III porphyrins: proof of intact ezymic conversion of the head-to-tail bilane into uro'gen-III by intramolecular rearrangement

Synthesis of doubly 13C-labelled forms of the unrearranged bilane (2) allows proof beyond doubt that the biosynthesis of natural porphyrins (and relatives) occurs by head-to-tail assembly of 4 PBG units followed by intramolecular rearrangement.

Synthesis of the isobacteriochlorin macrocycle: a photochemical approach

The isobacteriochlorin macrocycle is synthesised by a mild route in which the key step is a photochemical cyclisation.

Synthesis of [11C]PBR170, a novel imidazopyridine, for imaging the translocator protein with PET

The translocator protein (TSPO) ligand 2-(6,8-dichloro-2-(4-ethoxyphenyl)imidazo[1,2-a]pyridin-3-yl)-N-(2-fluoropyridin-3-yl)-N-methylacetamide (PBR170), is a novel imidazopyridineacetamide with high affinity (2.6 nm) and selectivity for the TSPO. The synthesis of [(11)C]PBR170 was accomplished by N-methylation of the corresponding desmethyl precursor with [(11)C]methyl iodide in the presence of sodium hydroxide in dimethylformamide. [(11)C]PBR170 was produced in 30-45% radiochemical yield (decay-corrected, based on [(11)C]methyl iodide) with a radiochemical purity >98% and a specific activity of 90-190 GBq/μmol after 35 min of synthesis time.

Biosynthesis of porphyrins and related macrocycles. Part 16. Proof that the single intramolecular rearrangement leading to natural porphyrins (type-III) occurs at the tetrapyrrole level

Ausgehend von den Komponenten (I) und (II) wird uber die Stufen (III), (V) und (VI) durch alkalische Hydrolyse von (VI) das Aminomethylbilan (VIIa) synthetisiert, dessen Cyclisierung auf chemischem Weg, hauptsachlich Uroporphyrinogen I (UP) (VIIIb), auf enzymatischem Weg dagegen hauptsachlich UP III (VIIIa) liefert.

Synthetic routes to C-methylated chlorins

The chemistry of nitroalkanes has been used to develop two rational synthetic routes to the new class of Cmethylated chlorins.