Kengo Sumi

Palladium(0)‐Mediated Rapid Methylation and Fluoromethylation on Carbon Frameworks by Reacting Methyl and Fluoromethyl Iodide with Aryl and Alkenyl Boronic Acid Esters: Useful for the Synthesis of [11C]CH3C‐ and [18F]FCH2C‐Containing PET Tracers (PET=Positron Emission Tomography)

A new synthetic methodology for the rapid methylation and fluoromethylation on aryl and alkenyl frameworks by using methyl and fluoromethyl iodide with an organoboronic acid ester has been developed under the simple and mild conditions of [Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/K(2)CO(3) (dba= dibenzylideneacetone) in DMF at 60 degrees C for 5 min (see scheme). This boron protocol provides a firm chemical basis for the synthesis of (11)C- and (18)F-incorporated PET tracers.The rapid methylation and fluoromethylation on aryl and alkenyl carbon frameworks by reacting methyl and fluoromethyl iodide with aryl and alkenyl boronates have been studied with the focus on the realization of the synthesis of [(11)C]CH(3)- and [(18)F]FCH(2)-labeled positron emission tomography (PET) tracers. The coupling of methyl iodide and pinacol phenylboronate (40 equiv) is accomplished in >91 % yield within 5 min at 60 degrees C under the conditions of [Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/K(2)CO(3) (0.5:2:2; dba=dibenzylideneacetone) in DMF. The reaction shows a high generality and is applicable to various types of aryl and alkenyl boronates, giving the corresponding methylated derivatives in high yields (80-99 %). This reaction is also useful for the rapid incorporation of the fluoromethyl group. Thus, this boron protocol provides a firm chemical basis for the synthesis of (11)C- and (18)F-incorporated PET tracers and can be used as a complementary method for [(11)C]methylation together with our previous and ongoing processes using organotributylstannanes.

Rapid methylation on carbon frameworks useful for the synthesis of 11CH3-incorporated PET tracers: Pd(0)-mediated rapid coupling of methyl iodide with an alkenyltributylstannane leading to a 1-methylalkene

The Pd(0)-mediated rapid coupling of methyl iodide with an excess of alkenyltributylstannane was examined with the aim of incorporating a short-lived 11C-labeled methyl group into a biologically significant organic compound with a 1-methylalkene unit for the synthesis of a PET tracer. Four sets of reaction conditions (A-D) were used, all performed in DMF at 60 degrees C for 5 min. Condition B, using CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuCl/K2CO3 (1:40:0.5:4-6:2:5), works well in almost all cases. Condition D, using CH3I/stannane/Pd2(dba)3/P(o-tolyl)3/CuX (X = Br, Cl, or I)/CsF (1:40:0.5-5:2-20:2-20:5-50), shows the best results with regard to general applicability to tin substrates, affording the corresponding methylated product in >90% yield based on consumption of methyl iodide. P(t-Bu)2Me was less effective than P(o-tolyl)3, particularly for alpha,beta-unsaturated carbonyl substrates. No regio- or stereoisomerization occurred under these reaction conditions. The efficiency of the protocol was demonstrated by synthesis of an 11C-methylated compound.

The Effect of the H-1152P, a Potent Rho-Associated Coiled Coil-Formed Protein Kinase Inhibitor, in Rabbit Normal and Ocular Hypertensive Eyes

Purpose: We wanted to determine the intraocular pressure (IOP)-lowering effect of H-1152P by utilizing a rabbit ocular hypertension-glaucoma model and normal eyes. H-1152P is a potent, Rho-associated, coiled, coil-forming protein kinase (ROCK) inhibitor. Methods: IOPs were monitored by a pneumatonometer in New Zealand White rabbits that were given topically administered H-1152P or vehicle alone. Animals were divided into four groups followed by topical administration of 0.1, 1.0, 10, and 28 mM H-1152P. To study the IOP-lowering effects on an elevated IOP model, a rabbit ocular hypertension model was created by water loading. All studies were carried out by monitoring of IOPs on H-1152P-administered right eyes and phosphate-buffered saline (PBS)-administered left eyes. Results: In normotensive IOP rabbits, topical administration of H-1152P significantly decreased IOPs by 46.1 ± 5.0% at 1% (28 mM) solution. This effect was dose dependent, as the maximum reduction of IOPs were observed between 60 and 90 min after topical administration (3.6 ± 0.9 mmHg, 5.4 ± 0.7 mmHg, 6.8 ± 0.7 mmHg, and 7.2 ± 1.9 mmHg at 0.1, 1.0, 10, and 28 mM H-1152P). In addition, in the rabbit ocular hypertension model, the topical administration of H-1152P (28 mM) significantly lowered IOPs starting at 30 minutes and lasting up to 300 minutes after water loading. The maximum IOP reduction, however, was observed at 90 minutes after water loading (10.6 ± 2.3 mmHg). No serious side effects were observedin ocular tissues except for some conjunctival congestion that shortly disappeared within 3 hours.Conclusion: Topical administration of H-1152P potently decreased rabbit normotensive IOPs in a dose-dependent manner, and the duration of the IOP lowering was also elongated in a dose-dependent manner. In addition, H-1152P has a potent IOP-lowering effect on an ocular hypertension model. These result suggested that H-1152P could be a candidate for the next generation of glaucoma therapy.

Pd0-Mediated Rapid Coupling between Methyl Iodide and Heteroarylstannanes: An Efficient and General Method for the Incorporation of a Positron-Emitting 11C Radionuclide into Heteroaromatic Frameworks†

The Pd(0)-mediated rapid trapping of methyl iodide with an excess amount of a heteroaryl-substituted tributylstannane has been investigated with the aim of incorporating a short-lived (11)C-labelled methyl group into the heteroaromatic carbon frameworks of important organic compounds, such as drugs with various heteroaromatic structures, in order to execute a positron emission tomography (PET) study of vital systems. The reaction was first performed by using our previously developed CH(3)I/stannane/[Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/CuCl/K(2)CO(3) (1:40:0.5:2:2:2) system in DMF at 60 degrees C for 5 min (conditions A), however, the reaction gave low yields for various heteroaromatic compounds. Increasing the amount of phosphine ligand (conditions B) led to a significant improvement in the yield, but the conditions were still not suitable for a range of basic heteroaromatic structures. Use of the CuBr/CsF system (conditions C) also provided a result similar to that obtained under conditions B with an increased amount of the phosphine. Thus, pyridine and related heteroaromatic compounds remained less reactive substrates. The problem was overcome by replacing the DMF solvent with N-methyl-2-pyrolidinone (NMP). The reaction in NMP at 60-100 degrees C for 5 min using a CH(3)I/stannane/[Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/CuBr/CsF (1:40:0.5:16:2:5) combination (conditions D) gave the methylated products in yields of more than 80 % (based on the reaction of CH(3)I) for all of the heteroaromatic compounds listed in this study. Thus, the combined use of NMP and an increased amount of phosphine is important for promoting the reaction efficiently. The use of this general approach to rapid methylation has been well demonstrated by the synthesis of the PET tracers 2- and 3-[(11)C]methylpyridines by using [Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/CuBr/CsF (1:16:2:5) in NMP at 60 degrees C for 5 min, which gives the desired products in HPLC analytical yields of 88 and 91 %, respectively.

Synthesis of 11C-labeled retinoic acid, [11C]ATRA, via an alkenylboron precursor by Pd(0)-mediated rapid C-[11C]methylation

Retinoids are a class of chemical compounds which include both natural dietary vitamin A (retinol) metabolites and active synthetic analogs. Both experimental and clinical studies have revealed that retinoids regulate a wide variety of essential biological processes. In this study, we synthesized (11)C-labeled all-trans-retinoic acid (ATRA), the most potent biologically active metabolite of retinol and used in the treatment of acute promyelocytic leukemia. The synthesis of (11)C-labeled ATRA was accomplished by a combination of rapid Pd(0)-mediated C-[(11)C]methylation of the corresponding pinacol borate precursor prepared by 8 steps and hydrolysis. [(11)C]ATRA will prove useful as a PET imaging agent, particularly for elucidating the improved therapeutic activity of ATRA (natural retinoid) for acute promyelocytic leukemia by comparing with the corresponding PET probe [(11)C]Tamibarotene (artificial retinoid).

IOP-lowering effect of isoquinoline-5-sulfonamide compounds in ocular normotensive monkeys.

Rho-associated coiled coil-formed protein kinase (ROCK) inhibitors are under development as a new class of antiglaucoma agents. Based on the potent ROCK inhibitor H-1152, previously developed by us, we explored the possibility of related compounds as antiglaucoma agents and synthesized seven types of H-1152-inspired isoquinoline-5-sulfonamide compounds (H-0103-H-0107, H-1001, H-1005). Although all of these compounds potently inhibited ROCK (IC50=18-48 nM), only H-0104 and H-0106 exerted strong intraocular pressure (IOP)-lowering effects into the eyes of monkeys. These results suggested the possibility that there is no direct relationship between ROCK inhibition and IOP-lowering effects, indicating that the initial screening of compounds based on ROCK inhibitory activity may be an unsuitable strategy for developing antiglaucoma agents with potent IOP-lowering effects.

Blood-brain barrier permeability of ginkgolide: Comparison of the behavior of PET probes 7α-[(18)F]fluoro- and 10-O-p-[(11)C]methylbenzyl ginkgolide B in monkey and rat brains.

The blood-brain barrier permeability of ginkgolide B was examined using positron emission tomography (PET) probes of a 18F-incorporated ginkgolide B ([18F]-2) and a 11C-incorporated methylbenzyl-substituted ginkgolide B ([11C]-3). PET studies in monkeys showed low uptake of [18F]-2 into the brain, but small amounts of [11C]-3 were accumulated in the parenchyma. Furthermore, when cyclosporine A was preadministered to rats, the accumulation of [18F]-2 in the rat brain did not significantly change, however, the accumulation of [11C]-3 was five times higher than that in the control rat. These results provide effective approaches for investigating the drug potential of ginkgolides.