Pd⁰‐Mediated Rapid Cross‐Coupling Reactions, the Rapid C‐[¹¹C]Methylations, Revolutionarily Advancing the Syntheses of Short‐Lived PET Molecular Probes

Abstract

Positron emission tomography is a noninvasive method for monitoring drug (or diagnostic) behavior and its localization on the target molecules in the living systems, including the human body, using a short-lived positron-emitting radionuclide. New methodologies for introducing representative short-lived radionuclides, (11)C and (18)F, into the carbon frameworks of biologically active organic compounds have been established by developing rapid C-[(11)C]methylations and C-[(18)F]fluoromethylations using rapid Pd(0)-mediated cross-coupling reactions between [(11)C]methyl iodide (sp(3)-hybridized carbon) and an excess amount of organotributylstannane or organoboronic acid ester having sp(2) (phenyl, heteroaromatic, or alkenyl), sp(alkynyl), or sp(3) (benzyl and cinnamyl)-hybridized carbons; and [(18)F]fluoromethyl halide (iodide or bromide) and an organoboronic acid ester, respectively. These rapid reactions provide a firm foundation for an efficient and general synthesis of short-lived (11)C- or (18)F-labeled PET molecular probes to promote in vivo molecular imaging studies.

Synthesis of 11C-Labeled Thiamine and Fursultiamine for in Vivo Molecular Imaging of Vitamin B1 and Its Prodrug Using Positron Emission Tomography

“…10 These reactions allow regioselective 11 C labeling through the formation of a C−C bond. A tri-nbutyltin-substituted thiazole precursor 5, a prerequisite for Pd 0 -mediated rapid C-[ 11 C]methylation, was prepared, as shown in Scheme 2.…”

<sup>11</sup>C-Labeling of the C(1)-C(10) Dihydroxy Acid Moiety for the Study on the Synthesis of Kulokekahilide-2 PET Tracer

“…Prior to actual synthesis of 11 C-incorporated 1, we investigated a model study using a partial structure. Here, we are particularly interested in introducing 11 C onto the methylene group of 2 as a 11 CH 3 by our rapid cross-coupling reaction [12], [17] between sp 2 vinyland sp 3 -carbon atoms using an organostannyl or boron precursor 3 (Scheme 1) where key step of synthetic strategy involves the preparation of precursor 3 derived from methyl ester 2.…”

Oxygen Activated, Palladium Nanoparticle Catalyzed, Ultrafast Cross‐Coupling of Organolithium Reagents

“…[1,18,19] Such am ethod would be complementary to the more often used electrophilic quenching of anucleophilic drug precursor with [ 11 C]iodomethane.T he presence of several nucleophilic sites in specific precursors often results in undesired (overalkylated) side products.W es elected the synthesis of [ 11 C]celecoxib to illustrate the usefulness of our method (Scheme 5). [20,21] Initially,w ee xplored the reaction of commercially available MeLi and celecoxib precursor 30.H aving isolated the target 31 in excellent yield (91 %), we used in situ generated MeLi, prepared from MeI in both astoichiometric and as ubstoichiometric (0.1 equiv) ratio with respect to nBuLi. [18] Gratifyingly,w ew ere able to isolate the corre-…”