Automated radiosynthesis of [¹¹C]MTP38—a phosphodiesterase 7 imaging tracer—using [¹¹C]hydrogen cyanide for clinical applications

Abstract

We have developed 8‐amino‐3‐(2S,5R‐dimethyl‐1‐piperidyl)‐[1,2,4]triazolo[4,3‐a]pyrazine‐5‐[11C]carbonitrile ([11C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [11C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [11C]MTP38 using [11C]hydrogen cyanide ([11C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [11C]MTP38 was performed using an automated 11C‐labeling synthesizer developed in‐house within 40 min after the end of irradiation. [11C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [11C]CO2 at the end of irradiation, decay‐corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/μmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [11C]MTP38 injection complied with our in‐house QC and quality assurance specifications. We successfully automated the radiosynthesis of [11C]MTP38 for clinical applications using an 11C‐labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [11C]MTP38 suitable for clinical applications.

Evaluation and improvement of CuI‐mediated 11C‐cyanation

“…1,10-Phenanthroline provided high RCY with electronwithdrawing substituents and no improvement in RCY with electron-donating substituents (Table 8, entries 9-12). In contrast, K 2 CO 3 exhibited tolerance to various substituents (Table 8, entry [13][14][15][16]. With the optimized conditions determined, subsequently, we analyzed the scope of the CuI-mediated 11 C-cyanation reaction for a variety of (hetero)aromatic bromides (Table 9).…”

“…We have also discovered that the same type of reaction proceeded using Cu(I) iodide (CuI) instead of the active Cu(I) species. This CuI‐mediated 11 C‐cyanation of (hetero)aryl bromides has been successfully applied for the synthesis of [ 11 C]AZD1283 (an antagonist for P2Y12 receptor) and [ 11 C]MTP38 (a PET imaging probe for phosphodiesterase 7 in the human brain) 14–17 . Previously, 11 C‐cyanation had been conducted by alkali metal [ 11 C]cyanides or hydrogen [ 11 C]cyanide, which is synthesized by the Pt‐catalyzed reaction of [ 11 C]methane with NH 3 at high temperatures, followed by the treatment of [ 11 C]NH 4 CN with alkali metals or strong acid.…”

“…This CuI-mediated 11 C-cyanation of (hetero)aryl bromides has been successfully applied for the synthesis of [ 11 C] AZD1283 (an antagonist for P2Y12 receptor) and [ 11 C] MTP38 (a PET imaging probe for phosphodiesterase 7 in the human brain). [14][15][16][17] Previously, 11 A wide variety of aryl bromides are commercially available and relatively stable in comparison to their corresponding iodides; however, bromides are poorly reactive for Cu-mediated cyanation reactions within a short time. Although organotin or organoboron compounds can be cyanated under mild reaction conditions, they are generally synthesized via transition-metal-catalyzed reactions of the corresponding halogenated compounds.…”