Abstract
2-((1E,3E)-4-(6-(11C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol (11C-PBB3) is a clinically useful PET probe that we developed for in vivo imaging of tau pathology in the human brain. To ensure the availability of this probe among multiple PET facilities, in the present study we established protocols for the radiosynthesis and quality control of 11C-PBB3 and for the characterization of its photoisomerization, biodistribution, and metabolism. Methods: 11C-PBB3 was synthesized by reaction of the tert-butyldimethylsilyl desmethyl precursor (1) with 11C-methyl iodide using potassium hydroxide as a base, followed by deprotection. Photoisomerization of 11C-PBB3 under fluorescent light was determined. The biodistribution and metabolite analysis of 11C-PBB3 was determined in mice using the dissection method. Results: 11C-PBB3 was synthesized with 15.4% ± 2.8% radiochemical yield (decay-corrected, n = 50) based on the cyclotron-produced 11C-CO2 and showed an averaged synthesis time of 35 min from the end of bombardment. The radiochemical purity and specific activity of 11C-PBB3 were 98.0% ± 2.3% and 180.2 ± 44.3 GBq/μmol, respectively, at the end of synthesis (n = 50). 11C-PBB3 showed rapid photoisomerization, and its radiochemical purity decreased to approximately 50% at 10 min after exposure to fluorescent light. After the fluorescent light was switched off, 11C-PBB3 retained more than 95% radiochemical purity over 60 min. A suitable brain uptake (1.92% injected dose/g tissue) of radioactivity was observed at 1 min after the probe injection, which was followed by rapid washout from the brain tissue. More than 70% of total radioactivity in the mouse brain homogenate at 5 min after injection represented the unchanged 11C-PBB3, despite its rapid metabolism in the plasma. Conclusion: 11C-PBB3 was produced with sufficient radioactivity and high quality, demonstrating its clinical utility. The present results of radiosynthesis, photoisomerization, biodistribution, and metabolite analysis could be helpful for the reliable production and application of 11C-PBB3 in diverse PET facilities.
Accumulation of intracellular tau fibrils is a neuropathologic hallmark of Alzheimer disease (AD) and related tau-positive neurodegenerative disorders, which are collectively referred to as tauopathies (1). Understanding of the mechanistic roles played by pathologic tau in AD and related tauopathies has stimulated increasing interest in the development of imaging probes that facilitate visualization of tau pathology in the brains of living humans and animal models of tauopathies (1). 18F-FDDNP (Fig. 1) was applied to PET imaging of intraneuronal neurofibrillary tangles for the first time (2). However, 18F-FDDNP showed a relatively low contrast and selectivity for tau lesions versus β amyloid in in vitro autoradiograms and PET images of AD brains (3). In addition to 18F-FDDNP, researchers have developed several promising PET probes for imaging tau protein in the brain (4–10). Among these radioprobes, 18F-T807, 18F-T808, 18F-THK523, and 18F-THK5105 (Fig. 1) have been used in clinical studies for AD patients (6,8–10), whereas its capability of capturing tau aggregates in non-AD tauopathies and transgenic animal models is yet to be determined.
Chemical structures of PET probes for imaging of tau pathology in clinical use.
Recently, we developed a new class of tau ligands, phenyl/pyridinyl butadienyl benzothiazoles/benzothiazoliums (PBBs). In vivo optical imaging of a transgenic mouse model demonstrated rapid and sensitive detection of intraneuronal tau inclusions by intravenous administration of these ligands, which are intrinsically fluorescent (11). Selected from these ligands, three 11C-labeled compounds were synthesized and evaluated for their potential as PET probes for imaging tau pathology in tau transgenic mouse models (11). After preclinical evaluation, 2-((1E,3E)-4-(6-(11C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol (11C-PBB3, Fig. 1) was applied to clinical PET studies and was demonstrated to effectively display tau pathology in patients with AD and non-AD tauopathies. Notably, the high-level retention of 11C-PBB3 in the AD hippocampus wherein tau pathology is enriched sharply contrasted with that of a β-amyloid PET probe, 11C-Pittsburgh compound B (11C-PIB) (11,12).
Our previous study was focused on the development of PBBs and the application of 11C-PBB3 to PET imaging of a mouse model and human brains (11). Meanwhile, the growing interest in the clinical use of 11C-PBB3 in many PET facilities motivated us to establish protocols for its radiosynthesis and quality control and to characterize its chemical stability and its pharmacokinetic and metabolic properties. Here, we determined the radiosynthetic conditions for 11C-PBB3 to obtain an appropriate amount of radioactivity with reliable quality for clinical application. Because of the chemical structure of pyridylbutadienylbenzothiazole in 11C-PBB3, which is considered to easily undergo photoisomerization by exposure to ultraviolet light (13), we monitored the progress of photoisomerization of 11C-PBB3 under fluorescent light and investigated how to prevent it during radiosynthesis and quality control. To validate whether the radioactive signals in the mouse and human brains were derived from 11C-PBB3 itself, we performed metabolite analysis of 11C-PBB3 for the mouse plasma and brain homogenate.
MATERIALS AND METHODS
General
PBB3 and its precursor (5-((1E,3E)-4-(6-(tert-butyldimethylsilyloxy)-benzo[d]thiazol-2-yl)buta-1,3-dienyl)pyridin-2-amine (1, Fig. 2) for radiosynthesis were synthesized and supplied from the NARD Institute. Commercially available reagents and organic solvents (Sigma-Aldrich and Wako Pure Chemical Industries) were used without further purification. 11C was produced by 14N(p, α)11C nuclear reaction using a CYPRIS HM18 cyclotron (Sumitomo Heavy Industries). Effluent radioactivity was monitored using a NaI (Tl) scintillation detector system (Gabi Star PET; Raytest). If not otherwise stated, radioactivity was determined using an IGC-3R Curiemeter (Aloka).
Radiosynthesis of 11C-PBB3.
Male ddY mice were purchased from Japan SLC Inc. Animals were maintained and handled in accordance with the recommendations of the U.S. National Institutes of Health and the guidelines of the National Institute of Radiologic Sciences. Animal experiments were approved by the Animal Ethics Committee of the National Institute of Radiologic Sciences. Male ddY mice (35.2 ± 2.2 g) were fed ad libitum.
Radiosynthesis of 11C-PBB3
11C-methyl iodide (11C-CH3I) was synthesized from cyclotron-produced 11C-CO2 using an automated synthesis system developed in-house (14). The produced 11C-CH3I was trapped in a mixture of the tert-butyldimethylsilyl group-protected desmethyl precursor 1 (0.9–1.1 mg) in anhydrous dimethylsulfoxide (0.15 mL) and KOH (10 mg) suspended in anhydrous dimethylsulfoxide (0.3 mL) at room temperature. Heating the reaction mixture at 125°C for 5 min produced 5-((1E,3E)-4-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-yl)buta-1,3-dienyl)-N-2-11C-methylpyridin-2-amine (11C-2). Subsequent deprotection of the tert-butyldimethylsilyl group in 11C-2 was performed using H2O (0.2 mL) at 50°C for 2 min. After 1.5 mL of the high-performance liquid chromatography (HPLC) solvent was added to the reaction vessel, the radioactive mixture was loaded into a preparative HPLC system (Jasco) for separation. The HPLC conditions were as follows: Atlantis T3 (5 μm, 10-mm internal diameter [i.d.] × 150 mm; Waters); acetonitrile/50 mM sodium phosphate buffer (pH 7.0) (20/30, v/v); 6.0 mL/min; 379-nm ultraviolet light. The fraction corresponding to 11C-PBB3 (retention time [tR], ∼7 min) was collected into a flask in which 25% ascorbic acid (0.4 mL) and polysorbate-80 (0.075 mL) in ethanol (0.3 mL) had been added before radiosynthesis, and was then evaporated to dryness. The residue was dissolved in physiologic saline (6–12 mL) and sterilized with a Millex-GS filter (Millipore). An amber vial was filled with the formulated product.
All radiosynthesis and subsequent quality control procedures were performed without fluorescent light to prevent photoisomerization of 11C-PBB3. If necessary, an ultraviolet-cutoff flashlight (green light, LED-41VIS525; OptoCode) was used to monitor these procedures for a short time.
Determination of Radiochemical Purity and Photoisomerization
With the fluorescent light switched off, the final product solution of 11C-PBB3 was analyzed using an HPLC system (515 pump and 2487 ultraviolet detector; Waters) and an XBridge Shield RP18 column (2.5 μm, 3.0 mm i.d. × 50 mm; Waters). A mixture of 90% aqueous acetonitrile and 50 mM ammonium phosphate buffer (pH 9.3) (50/50 [0–1.2 min] and then 70/30 [1.2 min and onward], v/v) was used as the mobile phase. The tR of 11C-PBB3 was approximately 1.1 min at 1.0 mL/min. The identity was confirmed by coinjection with an authentic PBB3 sample. The specific activity was calculated by comparison of the assayed radioactivity to the carrier mass, which was measured on the basis of its ultraviolet peak at 379 nm. To determine the radiochemical stability of 11C-PBB3, the formulated product was maintained for 60 min at room temperature without fluorescent light. An analytic sample was taken from the formulated solution to measure the radiochemical purity again.
For comparison, a portion of the 11C-PBB3 injection sample was transferred to a colorless vial and maintained for 60 min at room temperature under fluorescent light. Analytic samples were taken from this vial to measure the radiochemical purity at 1, 10, and 60 min.
Quality Control
In addition to determination of radiochemical purity and specific activity, the physical appearance of the 11C-PBB3 injection was checked by visual inspection (15). pH was measured using a pH meter (F-71; Horiba) and a probe (9618-10D; Horiba). Sterility was tested using a soybean-casein digest broth (Merck) incubated with the injection sample at 20°C–25°C for 14 d and fluid thioglycollate medium (Merck) incubated with the sample at 30°C–35°C for 14 d. Absence of culture growth after 14 d indicates sterility (16). The endotoxin content in the injection sample was measured using a toxinometer (ET-6000; Wako) (17). Residual organic solvents (acetonitrile and ethanol) were measured using a gas chromatography system (7890; Agilent Technologies) (18). A DB-WAX column (0.50 μm, 0.53-mm i.d. × 30 m; Agilent Technologies) was maintained at 40°C (0–8 min), raised to 120°C (8–28 min), and kept at 120°C (28–33 min). The makeup gas was nitrogen (99.9995%, 50 mL/min), and the carrier gas was helium (99.995%, 4 mL/min). A flame ionization detector was used.
Biodistribution Study
11C-PBB3 (1.6 MBq in 0.1 mL, 49.6 GBq/μmol) was injected into the tail vein of mice (n = 4 for each time point) without fluorescent light. The blood, heart, lung, spleen, liver, small intestine, testis, kidney, muscle, and brain were dissected at 1, 5, 15, 30, and 60 min after injection. The radioactivity in each tissue was measured using a γ counter (1480 Wizard 3; Perkin-Elmer) and expressed as follows: uptake [percentage injected dose (%ID)/g] = [tissue radioactivity (cps) × 100/tissue weight (g)]/injected dose (cps). All measured radioactivity values were corrected for decay.
Metabolite Analysis in Brain and Plasma
11C-PBB3 (33.3–37 MBq in 0.1–0.2 mL, 51.9 ± 18.2 GBq/μmol) was injected into the tail vein of mice (n = 3 for each time point), and the mice were sacrificed by cervical dislocation at 1 and 5 min after injection. Blood samples were obtained and centrifuged at 15,000 rpm for 1 min at 4°C. The plasma (0.5 mL) was separated and transferred to a tube containing acetonitrile (0.5 mL). The mixture was stirred in a vortex mixer and centrifuged at 15,000 rpm for 2 min to separate the precipitate from the aqueous phase.
The half brain was placed in test tubes, each containing 2.5 mL of ice-cooled saline, and homogenized (SilentCrusher-S; Heidolph Instruments). Radioactivity (%ID/g) in the left brain was measured at the same time. The homogenized brain tissue (0.5 mL) was transferred to a tube containing acetonitrile (0.5 mL) and centrifuged (15,000 rpm, 2 min, 4°C). The precipitate and supernatant were separated and measured for radioactivity. The supernatants of the plasma and brain homogenates were analyzed using an HPLC system equipped with a highly sensitive detector for radioactivity (19). The HPLC system and conditions were as follows: pump, PU-2089 plus (Jasco); ultraviolet detector, UV-2075 (Jasco); NaI(Tl) scintillation detector (S-2493A; OKEN); precolumn, XBridge Prep C18 Guard Cartridge (5 μm, 10 mm i.d. × 10 mm; Waters); main column, XBridge OST C18 (2.5 μm, 10 mm i.d. × 50 mm; Waters); mobile phase, 90% aqueous acetonitrile/0.02 M sodium phosphate buffer (pH 7.0) (30/70 [0–4 min], 40/60 to 70/30 [4–7 min], v/v); flow rate, 8.0 mL/min; tR, 11C-PBB3, 5 min. All the procedures in this section were conducted with the fluorescent light switched off.
RESULTS
Radiosynthesis of 11C-PBB3
11C-PBB3 was synthesized by N-methylation of the desmethyl precursor 1 with 11C-CH3I using KOH as a base (Fig. 2), followed by deprotection of the tert-butyldimethylsilyl group in the intermediate 11C-2 with water. After the reaction, HPLC separation (Fig. 3), and formulation, 11C-PBB3 was successfully obtained with a sufficient amount of radioactivity. At the end of synthesis, 11C-PBB3 of 1.6–3.1 GBq was obtained as an injectable solution of sterile normal saline after 30–35 min of proton bombardment at a beam current of 18 μA. The decay-corrected radiochemical yield of 11C-PBB3 based on 11C-CO2 was 15.4% ± 2.8% (n = 50) at the end of bombardment, and the specific activity was 180.2 ± 44.3 GBq/μmol (n = 50) at the end of synthesis. The averaged radiochemical purity of the 11C-PBB3 product in an amber vial was 98.0% ± 2.3% (Fig. 4A) and remained greater than 95% after 60 min (Fig. 4B) without fluorescent light. The total synthesis time was approximately 35 min from the end of bombardment.
Typical preparative HPLC chromatogram of 11C-PBB3.
Typical analytic HPLC chromatograms of 11C-PBB3. Analyses were performed without (A and B) and with (C–E) fluorescent light. Identity of 11C-PBB3 was confirmed by coinjection with authentic PBB3 sample immediately after formulation (A) and at 60 min (B), 1 min (C), 10 min (D), and 60 min (E).
Photoisomerization
Figures 4C–4E show the photoisomerization of 11C-PBB3 in a colorless vial under fluorescent light. At 1 min after exposure to the fluorescent light, the radiochemical purity of 11C-PBB3 decreased to 77%. From 10 to 60 min, its radiochemical purity remained approximately 50%. The chemical structure of the 11C-impurity was not identified but was assumed to be the Z, Z or E, Z isomer of 11C-PBB3.
Quality Control
Table 1 summarizes the results of the quality control assessment for 3 different lots of 11C-PBB3 production. The physical appearance of the product was clear and without particles. The pH was 6.7 ± 0.8. In sterility testing, no viable bacteria or microorganisms were observed in soybean-casein digest broth or fluid thioglycollate medium. The endotoxin content was undetectable (<0.7 endotoxin units/maximum volume). The radiochemical purity of 11C-PBB3 was 98.2% ± 2.2% (n = 3) at the end of synthesis and was within the range of 97.0% ± 0.8% after 60 min. The residual amounts of ethanol and acetonitrile in the 11C-PBB3 injection sample were to be 6.7 ± 0.6 ppm and 1 ppm, respectively.
Quality Control for 11C-PBB3 Productions (n = 3)
Biodistribution Study
Table 2 shows the tissue distribution of radioactivity in the whole body of mice at 1, 5, 15, 30, and 60 min after injection of 11C-PBB3. Uptake in most tissues was the highest at 1 min among all sampling time points. The radioactivity levels in the blood, heart, lung, testis, muscle, and brain decreased rapidly after initial uptake, whereas the radioactivity in the liver, spleen, small intestine, and kidney reduced gradually after 5 min. The radioactivity in all tissues except the small intestine cleared to less than 1 %ID/g at 60 min. Brain uptake was 1.92 %ID/g at 1 min and then decreased rapidly to 0.03 %ID/g at 60 min.
Biodistribution for 11C-PBB3 in Mice
Metabolite Analysis in Brain and Plasma
Figure 5 shows the HPLC chromatograms for the plasma and brain homogenate samples after injection of 11C-PBB3. In the plasma, the percentage of 11C-PBB3 rapidly decreased and a radiolabeled metabolite was observed as early as 1 min after injection (Fig. 5A). The fraction corresponding to unchanged 11C-PBB3 in the plasma was 1.9% ± 0.53% at 5 min (Fig. 5B) and was not detectable at 15 min (data not shown). The radiolabeled metabolite was more polar than 11C-PBB3, as estimated by its tR (2.0 min) on the HPLC charts. Despite the rapid metabolism in plasma, the percentage of unchanged 11C-PBB3 in the brain homogenate was 82% at 1 min (Fig. 5C) and 70% at 5 min (Fig. 5D). A radiolabeled metabolite was also detected in the HPLC charts of the brain samples, and its tR was similar to that of the metabolite in the plasma. Calculated from the total brain uptake (%ID/g), which was simultaneously measured for the same mice, radioactivity levels representing unchanged 11C-PBB3 and 11C-metabolite in the brain were found to be 1.58 ± 0.25 and 0.35 ± 0.06 %ID/g, respectively, at 1 min and 0.83 ± 0.06 and 0.35 ± 0.04 %ID/g, respectively, at 5 min. Recovery of radioactivity from HPLC analysis for all samples was greater than 95%. Because of the low radioactivity level, no further metabolite analysis was performed for the brain samples collected beyond 5 min.
HPLC chromatograms for metabolite analysis of 11C-PBB3 at 1 min in mouse plasma (A), at 5 min in mouse plasma (B), at 1 min in mouse brain (C), and at 5 min in mouse brain (D).
DISCUSSION
In this study, 11C-PBB3, a PET probe clinically used for imaging tau pathology in the human brain, was reliably synthesized with sufficient radioactivity and high quality. The metabolite analysis demonstrated the presence of unchanged 11C-PBB3 as the major radiolabeled component in the mouse brain despite its rapid metabolism in the plasma.
For the radiosynthesis of 11C-PBB3, the tert-butyldimethylsilyl group-protected desmethyl compound 1 was designed as the precursor. 11C-methylation of 1 and subsequent deprotection of 11C-2 gave 11C-PBB3 in a 2-step, 1-pot process (Fig. 2). We initially attempted to perform 11C-methylation of 1 using 11C-CH3OTf and no base, as is done for the synthesis of 11C-Pittsburgh compound B, which was easily labeled by direct 11C-methylation without requiring a base (20). However, this approach could not produce 11C-2, indicating that the α-amino group in the pyridine ring of 1 did not have enough nucleophilicity to undergo 11C-methylation without a base. Use of organic bases gave only trace amounts of 11C-2. Because the low labeling efficiency with 11C-CH3OTf without a base could not be improved even by heating the reaction mixture to 150°C for 5 min, this approach was not pursued further.
We then used KOH powder as a base to form the salt of the amine group in situ for the 11C-methylation of 1 with 11C-CH3I. The reaction conditions, including the amount of KOH, reaction solvent, time, and temperature, were optimized. It was found that the use of 10 mg of KOH, which was suspended in anhydrous dimethylsulfoxide for 20–30 s with an ultrasonic cleaner just before the synthesis, for reaction of 1 mg of 1 with 11C-CH3I at 125°C for 5 min could give the highest yield of 11C-2.
To remove the protective tert-butyldimethylsilyl group in 11C-2, we initially used tetrabutylammonium fluoride. Although the deprotection was successful, perfect removal of tetrabutylammonium fluoride and its decomposing residues in the final formulated product remained challenging. In place of tetrabutylammonium fluoride, we then used water to remove the tert-butyldimethylsilyl group. As expected, deprotection with alkali water at 50°C for 2 min proceeded perfectly. Indeed, alkali water was also used to remove the tert-butyldimethylsilyl group in the synthesis of 11C-AZD2184, an imaging agent for β amyloid with structural similarity to 11C-PBB3 (21).
Photoisomerization is a molecular behavior in which a structural change between isomers occurs because of photoexcitation. E and Z conversion is a representative behavior. Chemicals exhibiting this conversion include stilbene and azobenzene, in which the rotation or inversion around the double bond affords the isomerization between the 2 states (13). 11C-PBB3 underwent rapid photoisomerization as a pyridylbutadienylbenzothiazole compound by exposure to fluorescent light as shown in the analytic HPLC charts (Figs. 4C–4E). Compared with 11C-PBB3, its 11C-isomer showed much less specific binding to tau in the brain sections of AD patients (Supplemental Fig. 1; supplemental materials are available at http://jnm.snmjournals.org). This photoisomerization could be prevented by switching off the fluorescent light. By cutting off all fluorescent light in the synthetic hot cell to perform the radiosynthesis, in particular HPLC separation and formulation, and using an amber vial to store the formulated product, 11C-PBB3 was reliably obtained with high radiochemical purity without isomerization and radiolysis. All the results of quality control for the 11C-PBB3 injection complied with our in-house quality control and quality assurance specifications (Table 1). These data have guaranteed a reliable supply of 11C-PBB3 with sufficient radioactivity and high quality for clinical application.
The results of the biodistribution study of 11C-PBB3 in mice suggest that the radioactivity might be cleared mainly via the hepatobiliary and intestinal reuptake pathways, with rapid washout from the body (Table 2). The present brain uptake indicates that 11C-PBB3 easily passed through the blood–brain barrier, which is related to its lipophilicity (calculated logD, 3.30) (11). The effective dose estimate for 11C-PBB3 was 3.28 μSv/MBq (Supplemental Table 1), which was comparable to that reported for other 11C-labeled probes, including 11C-Pittsburgh compound B (4.7 μSv/MBq) (22).
Metabolite analysis demonstrated that this probe was rapidly decomposed to a polar radiolabeled metabolite in the plasma (Fig. 5). Despite the high abundance in the plasma, this metabolite, which was more hydrophilic than 11C-PBB3, showed limited entry into the brain. This finding indicates that uptake of radioactivity into the mouse brain was attributable mainly to unchanged 11C-PBB3. The present data, taken together with the results of the previous metabolite analysis for human plasma (11), demonstrated that 11C-PBB3 is rapidly metabolized to the same radiolabeled metabolite in mouse and human plasma, as evidenced by the similar tRs in the HPLC charts for plasma samples from these 2 species. The percentage of unchanged 11C-PBB3 in human plasma at 3 min after injection was 7.8% ± 2.2%, and the metabolizing rate in human plasma was slightly slower than that in mouse plasma. These results indicate that the radioactive signals acquired by PET in the human brain may primarily reflect the kinetics of 11C-PBB3. However, the influence of the low-grade uptake of radioactive metabolites into the brain on pharmacokinetic measures of 11C-PBB3 should be clarified.
In both humans and mice, the rapid entry of 11C-PBB3 into the brain and prompt reduction of the parent probe in the plasma imply that the levels of 11C-PBB3 in the brain may be dependent largely on its first-pass extraction (11). This characteristic, along with its minimal nonspecific binding of 11C-PBB3 to the myelin-rich components (11), resulted in a rapid washout of this probe from the brain, thereby reducing the background signal in the brain. Moreover, the significant contribution of the first-pass extraction to the radioprobe kinetics in the brain indicates that regional cerebral blood flow may be a critical determinant of the amount of 11C-PBB3 entering the brain; accordingly, the specific binding of 11C-PBB3 to tau lesions may be underestimated in areas with profound hypoperfusion. In fact, PET imaging with 11C-PBB3 in the AD brain displayed high-contrast signals in the hippocampus and low nonspecific retention in the white matter and other myelin-rich regions (11). Although the brain uptake of 11C-PBB3 is lower than that of 18F-T807 and 11C-Pittsburgh compound B (5,11,23), a relatively low concentration of free 11C-PBB3 in the brain may be advantageous to its selective binding to high-affinity, low-capacity sites on tau fibrils, compared with the low-affinity, high-capacity binding sites on β amyloid (11).
A shortcoming of 11C-PBB3 may be the presence of the radiolabeled metabolite in the mouse brain, although brain uptake of this metabolite was lower than that of unchanged 11C-PBB3 in the brain. Determination of the metabolic pathway for 11C-PBB3 is currently ongoing and should provide clues for the design of new probes with improved biostability. Identification of the chemical structure of the major 11C-PBB3 metabolite should also be performed, and subsequent radiolabeling of this metabolite would facilitate evaluation of its plasma and brain kinetics and affinity for tau fibrils.
CONCLUSION
11C-PBB3, a clinically useful PET probe for tau pathology in the brains of humans and transgenic mouse models, was successfully synthesized by reaction of tert-butyldimethylsilyl desmethyl precursor 1 with 11C-CH3I in the presence of KOH, followed by deprotection with water. We have so far achieved more than 200 productions of 11C-PBB3 in our facility for various research purposes, including translational PET imaging of mouse models and clinical PET assessments of patients diagnosed as having AD and non-AD neurodegenerative disorders. The present results demonstrate the reliable production and widespread clinical potential of 11C-PBB3.
DISCLOSURE
The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. This study was funded in part by Grants-in-Aid for the Japan Advanced Molecular Imaging Program, Scientific Research (B) (23390235), Core Research for Evolutional Science and Technology, and Scientific Research on Innovative Areas (Brain Environment) (23111009) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. Drs. Suhara, Higuchi, and Zhang are named as inventors on patent application 0749006WO1, claiming subject matter related to the results described in this paper. No other potential conflict of interest relevant to this article was reported.
Footnotes
Published online Jun. 24, 2014.
- © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
REFERENCES
- Received for publication February 24, 2014.
- Accepted for publication May 19, 2014.
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