Pd0–Mediated Rapid C–[11C]Methylation and C–[18F]Fluoromethylation: Revolutionary Advanced Methods for General Incorporation of Short–Lived Positron–Emitting 11C and 18F Radionuclides in an Organic Framework

Green Process of Three-Component Prostaglandin Synthesis and Rapid ¹¹C Labelings for Short-Lived PET Tracers

“…Here, the conjugate addition was performed by using the newly devised organocopper reagent [12] and the protected (R)-4-hydroxy-2-cyclopentanone (2) at 1:1 ratio in order to avoid the presence of extra nucleophiles in the reaction system. The combination of this conjugate addition and the trapping of the resulting metalated enolate with an excess amount of α-side chain iodide (4) in the presence of HMPA and (C 6 H 5 ) 3 SnCl led to the successful construction of a whole PG skeleton [9,13]. Thus, the metalated ω-side chain (3) was prepared in situ by treating the corresponding ω-side chain iodide with tert-C 4 H 9 Li (2 equiv) followed by the addition of CuI-(n-C 4 H 9 ) 3 P (1:2.6 equiv ratio) at À78 C in THF.…”

“…A PET probe thus obtained must be highly pure; the PET probe for clinical use should be synthesized at the Good Manufacturing Practice (GMP) level according to the regulation guidelines (also see Section 5). [3,4] as it has a number of advantages: (1) the [ 11 C]methyl group attached to the C atom is much more stable metabolically, thus providing a highly credible PET image; (2) a methyl group is the smallest non-polar substituent with the least influence on the parent biological activity; (3) short half-lived 11 C is favorable to rapidly screen optimized reaction conditions and ready evaluation of in vivo behavior allows several trials per day. These attractive features and benefits prompted us to investigate the realization of four types of rapid C-[ 11 C]methylations on organic frameworks involving arene, alkene, alkyne, and alkane, namely cross-coupling reactions between sp 2 (aryl) and sp 3 (alkyl) hybridized carbons, sp 2 (alkenyl) and sp 3 (alkyl) carbons, sp (alkynyl) and sp 3 (alkyl) carbons, and sp 3 (alkyl) and sp 3 (alkyl) carbons ( Figure 9).…”

“…In order to promote non-invasive dynamic in vivo molecular science such as a PET study, many efforts to accelerate the rate of the reaction are needed for labeling organic molecules with short-lived radioisotopes. Described herein are highly polished and potentiated novel C-couplings developed by our group in the course of long-term tight collaboration of chemistry, biology, and medicine [1][2][3][4][5].…”

“…DMF may stabilize such Pd intermediates even at high temperatures. It was very difficult to conduct the Stille reaction using CH 3 I as an sp 3 -carbon partner[39] until our successful attempt in this field[3,4]. Prabhakaran et al used our reaction conditions for the synthesis of [ 11 C]celecoxib using a tributyltin substrate after protecting the sulfonamide group[46].…”