Synthesis and biological evaluation of [¹¹C]AZ12504948; a novel tracer for imaging of glucokinase in pancreas and liver.

INTRODUCTION: Glucokinase (GK) is potentially a target for imaging of islets of Langerhans. Here we report the radiosynthesis and preclinical evaluation of the GK activator, [(11)C]AZ12504948, for in vivo imaging of GK. METHODS: [(11)C]AZ12504948 was synthesized by O-methylation of the precursor, AZ125555620, using carbon-11 methyl iodide ([(11)C]CH3I). Preclinical evaluation was performed by autoradiography (ARG) of human tissues and PET/CT studies in pig and non-human primate. RESULT: [(11)C]AZ12504948 was produced in reproducible good radiochemical yield in 28-30 min. Radiochemical purity of the formulated product was >98% for up to 2 h with specific radioactivities 855 ± 209 GBq/µmol (n=8). The preclinical evaluation showed some specificity for GK in liver, but not in pancreas. CONCLUSION: [(11)C]AZ12504948 images GK in liver, but the low specificity impedes the visualization of GK in pancreas. Improved target specificity is required for further progress using PET probes based on this class of GK activators.

Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography.

BACKGROUND: Atherosclerotic plaque rupture is usually a consequence of inflammatory cell activity within the plaque. Current imaging techniques provide anatomic data but no indication of plaque inflammation. The glucose analogue [18F]-fluorodeoxyglucose (18FDG) can be used to image inflammatory cell activity non-invasively by PET. In this study we tested whether 18FDG-PET imaging can identify inflammation within carotid artery atherosclerotic plaques. METHODS AND RESULTS: Eight patients with symptomatic carotid atherosclerosis were imaged using 18FDG-PET and co-registered CT. Symptomatic carotid plaques were visible in 18FDG-PET images acquired 3 hours post-18FDG injection. The estimated net 18FDG accumulation rate (plaque/integral plasma) in symptomatic lesions was 27% higher than in contralateral asymptomatic lesions. There was no measurable 18FDG uptake into normal carotid arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas of the plaque. CONCLUSIONS: This study demonstrates that atherosclerotic plaque inflammation can be imaged with 18FDG-PET, and that symptomatic, unstable plaques accumulate more 18FDG than asymptomatic lesions.

Syntheses of the first endothelin-A- and -B-selective radioligands for positron emission tomography.

We have synthesized two potential positron emission tomography (PET) radioligands for the endothelin (ET) receptor. [11C]-PD156707 was produced by O-methylation of PD169390 using [11C]iodomethane. Radiochemical conversions of the order of 74 +/- 3.2% (n = 8) were obtained. The radiochemical purity of the isolated [11C]-PD156707 was 99% and the specific activity was 538 mCi/micromol. [18F]-BQ3020 was produced from [18F]fluoride in a total radiochemical yield of 2.7 +/- 0.4% (n = 10) in 238 +/- 5 min. The radiochemical purity was 95% and specific activities of the order of 670-930 mCi/micromol were obtained.

In vivo evaluation of the biodistribution of 11C-labeled PD153035 in rats without and with neuroblastoma implants.

The biodistribution of 11C-labeled 4-(3-bromoanilino)-6,7-dimethoxyquinazoline, an inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase, has been evaluated in vivo in rats using positron emission tomography (PET). Time-activity data obtained after i.v. administration in one rat revealed that the radiotracer rapidly cleared from plasma with subsequent uptake in major organs of the body (brain, heart, liver, gastrointestinal tract and bladder). Uptake in proliferating tissue in rats with human neuroblastoma xenografts indicate that [O-11C-methyl]PD153035 shows promise as a new agent for in vivo imaging of tumors with PET.

Positron emission tomography compared with magnetic resonance imaging and computed tomography in supratentorial gliomas using multiple stereotactic biopsies as reference.

Ten patients with findings at computed tomography (CT) suggesting intracranial supratentorial glioma were investigated to compare the diagnostic efficacy of this technique with that of positron emission tomography (PET) using 11C-methionine and examinations with magnetic resonance (MR). The findings were related to histopathologic examination of serial stereotactic biopsies, which were guided by the appearance of the lesions on PET examination. To obtain corresponding slice orientation with the different examination techniques, an individually shaped helmet fixation was used. However, in 3 cases this fixation device could not be used for MR. Histopathologic diagnosis, obtained in all cases from multiple target stereotactic biopsies, included glioma in 9 patients and reactive gliosis in one case. A detailed comparison of the three imaging techniques and the findings at stereotactic biopsies was possible in 7 patients, while in 3 patients comparison with MR was less exact due to the patient's refusal to wear the helmet during this examination. MR was the most accurate method for outlining the total extent of a lesion, i.e. the tumor and the edema surrounding it. Four lesions had homogeneous signal characteristics and in 6 lesions two (or more) compartments could be distinguished with MR. In 5 cases the MR findings were in complete agreement with the histopathologic findings. However, a thorough correlation between signal characteristics and histology was not possible. Using PET the occurrence and the extent of tumor tissue was correctly predicted in 7 patients. The PET was normal in one case. Findings at CT were in agreement with the histopathologic diagnosis in 5 patients. MR was the most sensitive method for the detection of lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Positron emission tomography with 11C-methionine and computed tomography of intracranial tumours compared with histopathologic examination of multiple biopsies.

A selected group of 36 patients with suspected supratentorial gliomas were investigated with positron emission tomography (PET) using 11C-methionine and transmission computed tomography (CT) before and after intravenous injection of contrast medium. Every examination was performed with the head fixed in a plastic helmet and a baseplate to guarantee that the slice orientation was the same at examinations with the two modalities and over time. Guided by the examinations, multiple stereotactic biopsies were performed with the biopsy instrument mounted on the baseplate. Regional accumulation of methionine was compared with histology of the corresponding samples and with attenuation before and after injection of contrast medium as well as mass effect on CT. Typically, there was a low attenuating lesion with a slight mass effect on CT. There was an increased accumulation compared with normal brain tissue in 31 cases of tumours and ordinary or decreased accumulation in 3 cases of tumours. In 22 cases with increased accumulation of methionine the extension of the tumour judged by PET corresponded with that of histology. In 4 cases tumour cells were found outside the area with pathologic methionine uptake. In 5 patients there were areas with increased methionine accumulation where no tumour cells were found. In 22 cases PET using methionine was more accurate than CT in defining the tumour boundaries as determined from the histologic findings. Four groups of biopsy specimens with different amounts of methionine accumulation are described. The uptake in a single biopsy gives good but not exact information about the histology of the specimen.

Comparison of the accumulation kinetics of L-(methyl-11C)-methionine and D-(methyl-11C)-methionine in brain tumors studied with positron emission tomography.

Five patients with glioma were examined with positron emission tomography after the administration of 11C-L-methionine and at a following day with 11C-D-methionine. The rates of accumulation of the tracers were determined in the tumor and in the normal brain tissue according to a graphical technique of Patlak et coll. The accumulation rates for L-methionine were on the average 2.4 times higher than those of D-methionine in the tumors. The corresponding ration for normal brain tissue was 2.3. It is concluded that in this group of tumors without obvious blood-tumor-barrier breakdown, a stereospecific process with similar properties as in the normal brain tissue, is responsible for the accumulation of the labelled methionine.

PET study of methionine accumulation in glioma and normal brain tissue: competition with branched chain amino acids.

Five patients with glioma were examined with positron emission tomography using ([11C]methyl)-L-methionine. The study was repeated while the patient was being infused with branched chain amino acids (BCAA), 250 mumol/min. The accumulation rates of methionine in tumor tissue and in normal brain tissue were compared without and with the infusion of amino acids. Both tumor tissue and normal brain tissue showed a reduction in the methionine accumulation by 35% while the patient received the infusion. In one patient with a severe blood-tissue barrier disruption the tumor accumulation rate was unaffected. It is concluded that in gliomas without severe blood-tissue barrier disruption, the accumulation of methionine is governed by processes exhibiting similar properties regarding competition with BCAA as in normal brain tissue.

The normal pituitary examined with positron emission tomography and (methyl-11C)-L-methionine and (methyl-11C)-D-methionine.

Four patients with radiologically normal pituitary gland were examined with positron emission tomography after the administration of (methyl-11C)-L-methionine. On a following day the examination was repeated with (methyl-11C)-D-methionine. The accumulation rate of L-methionine in the pituitary was measured, giving a value that was about twice that of normal brain tissue. The accumulation rate of D-methionine in the pituitary was almost a factor of 10 lower than that of L-methionine. In the normal brain tissue that ratio was 2.3. The study clearly indicates that the methionine uptake in the pituitary is stereospecific. 11C-D-methionine is freely distributed in the tissue without entrapment, whereas 11C-L-methionine is irreversibly bound. It is concluded that PET with 11C-L-methionine can be used to study amino acid utilization in the pituitary.

11C-labelled glycine: synthesis and preliminary report on its use in the investigation of intracranial tumours using positron emission tomography.

Carbon-11-labelled glycine has been prepared by a Bücherer-Strecker synthesis using [11C]cyanide, formaldehyde and ammonium carbonate. Total synthesis time, including chromatographic purification, was 30-35 min from end-of-bombardment. Radiochemical yield was 35%, based on [11C]cyanide and radiochemical purity was shown to be greater than 98% by analytical HPLC. The 11C-labelled glycine thus prepared was used along with [68Ga]EDTA and L-[methyl-11C]methionine in the visualization of an anaplastic astrocytoma by positron emission tomography.

The preparation of 11C-labelled fluoromethane for the study of regional cerebral blood flow using positron emission tomography.

Fluoromethane, previously labelled with 18F and used as a tracer in the measurement of regional cerebral blood flow, was 11C-labelled by the reaction of 11C-methyl iodide with tetraethylammonium fluoride. Sufficient quantities of radiotracer were prepared with a minimum amount of handling from 15 min target irradiations in the 14N(p, alpha)11C reaction. Total synthesis time was 25 min from end-of-bombardment, allowing serial blood flow measurements 30 min apart. The use of 11C-fluoromethane as a cerebral blood flow tracer in positron emission tomography is discussed.

11C-labeled 4-isopropylantipyrine: preparation and biological evaluation as a blood flow tracer in positron emission tomography (PET).

Radiolabeled 4-isopropylantipyrine (1) has been synthesized and evaluated as a tracer for the measurement of cerebral blood flow (CBF). Methylation of 4-isopropyl-3-methyl-1-phenylpyrazol-5-one (2) with [14C]methyl iodide in acetonitrile gave [14C]-1 in radiochemical yields of 10-20%. Its blood-brain partition coefficient in rats was determined to be 0.62 +/- 0.03 (mean +/- SE). Autoradiographic determination of regional cerebral blood flow under normal flow conditions indicated that [14 C]-1 gives results essentially identical with those obtained with the widely used tracer [14C]-4-iodoantipyrine ( [14C]-IAP). Studies performed in high-flow states indicated that [14C]-1 is not more diffusion limited than [14C]-IAP. A rapid synthesis was therefore developed for the preparation of [11C]-1. Radiochemical yields were increased to 40-50% when the alkylation of 2 with [11C]methyl iodide was performed in dimethyl sulfoxide using solid potassium hydroxide as a base. Since the 11C-labeled compound can easily be produced in large quantities and since the tracer is not diffusion limited at flow rates commonly observed in normal and most pathological states in man, [11C]-4-isopropylantipyrine will be used for in vivo studies of CBF using positron emission tomography.

Preparation of 11C-labelled Raclopride, a new potent dopamine receptor antagonist: preliminary PET studies of cerebral dopamine receptors in the monkey.

A new dopamine receptor antagonist, Raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy- 6-methoxybenzamide, FLA 870) (1), has been labelled using [11C]ethyl iodide for alkylation of the nitrogen of the pyrrolidine ring in the corresponding secondary amine (5). The synthesis of 5 and an efficient method for the preparation of [11C]ethyl iodide are described. The 11C-labelled FLA 870 (1) was purified by HPLC and then used in positron emission tomography to visualize the dopamine receptor-rich areas of the monkey brain. The images obtained show selective accumulation of FLA 870 in striatum and a 10-fold separation between the binding to caudate vs cerebellum.

11C-2-deoxy-D-glucose: synthesis and preliminary comparison with 11C-D-glucose as a tracer for cerebral energy metabolism in PET studies.

11C-2-Deoxy-D-glucose has been prepared by the reaction of 11C-hydrogen cyanide with a stable precursor, 1-deoxy-2,3:4,5-di-O-isopropylidine-1-iodo-D-arabitol, thereby avoiding the synthesis of starting material immediately prior to labeling. Fast, efficient, and reproducible solvent change from dimethyl sulfoxide to ether by flash chromatography enabled the use of diisobutylaluminium hydride in the reduction of the intermediate nitrile. Hydrolysis of the imine-aluminum complex with sulfuric acid, removal of the isopropylidine protecting groups with formic acid, and HPLC purification with an Aminex HPX-87P column yielded 11C-2-deoxy-D-glucose in an aqueous solution, sterile, pyrogen-free, and ready for use in human studies. The radiochemical yield was approximately 20% after a synthesis time of 50 min. The 11C-2-deoxy-D-glucose thus obtained is presently being compared with photosynthetically prepared 11C-D-glucose in PET studies of cerebral metabolism. A preliminary report of the regional cerebral metabolic rate of glucose obtained with the two tracers in a healthy subject with visual stimulation is presented.