K. Ishiwata

Mapping of histamine H1 receptors in the human brain using [11C]pyrilamine and positron emission tomography

We have studied the characteristics of carbon‐11 labeled pyrilamine as a radioligand for investigating histamine H1 receptors in human brain with positron emission tomography (PET). [11QPyrilamine is distributed evenly in proportion to cerebral blood flow at initial PET images. Later (after 45–60 min), 11C radioactivity was observed at high concentrations in the frontal and temporal cortex, hippocampus, and thalamus, and at low concentrations in the cerebellum and pons. The regional distribution of the carbon‐11 labeled compound in the brain corresponded well with that of the histamine H1 receptors determined in vitro in autopsied materials. In six controls, the frontal and temporal cortices/cerebellum ratio increased during the first 60 min to reach a value of 1.22 ± 0.071. Intravenous administration of d‐chlorpheniramine (5 mg) completely abolished the specific binding in vivo in the frontal cortex and temporal cortex (cortex/cerebellum ratio, 0.955 ±0.015). The availability of this method for measuring histamine H1 receptors in vivo in humans will facilitate studies on neurological and psychiatric disorders in which histamine H1 receptors are thought to be abnormal.

Synthesis and radiation dosimetry of 4-borono-2-[18F]fluoro-D,L-phenylalanine: a target compound for PET and boron neutron capture therapy.

The 18F-labeling of 4-borono-D-L-phenylalanine (BPA), a potential target compound for cancer treatment with boron neutron capture therapy, is described. By direct fluorination of BPA with [18F]AcOF or [18F]F2 followed by HPLC separation, 4-borono-2-[18F]fluoro-D,L-phenylalanine was prepared with radiochemical yields of 25-35% and with a radiochemical purity of over 99%. The tissue distribution study showed that the compound has potential as a tracer for pancreas imaging with positron emission tomography. Radiation dosimetry is also described.

Histamine H1 receptors in human brain visualized in vivo by [11C]doxepin and positron emission tomography

Histamine H1 receptors in the living human brain were visualized by positron emission tomography (PET) using [N-11C-methyl]-(E)-doxepin ([11C]doxepin). The regional distribution of the carbon-11-labeled compound in the brain corresponded well with that of the histamine H1 receptors measured in vitro using [3H]pyrilamine. The radioactivity in the brain was significantly reduced by intravenous pretreatment with d-chlorpheniramine (5 mg), a histamine H1 antagonist. The regional distribution of [11C]doxepin in the brain 45-90 min after its injection was almost the same as that of [11C]pyrilamine in the brain. These results indicate that [11C]doxepin is useful for measuring histamine H1 receptors in human brain by PET.

Evaluation of the treatment response of lung cancer with positron emission tomography and l-[methyl-11C]methionine: a preliminary study

We carried out a study to evaluate treatment response and residual mass in lung cancer with positron emission tomography (PET), using l-[methyl-11C]methionine (MET). MET tumour uptake and tumour volume measured by computed tomography (CT) before and within 2 weeks after radiotherapy or chemoradiotherapy were compared in 43 studies of 21 patients. Ten patients with local control (no recurrence) of tumour showed a larger decrease in MET uptake (65.2%±12.2%) than in tumour volume (50.8%±9.6%, P<0.01). Five patients with early recurrence (from 1 to 4 months) showed smaller decreases in both MET uptake (22.2%±13.5%) and tumour volume (28.6%±20.0%) than those in the no-recurrence group (P<0.01). Four patients with late recurrence (after 11 months or more) showed a similar decrease to the no-recurrence group in MET uptake (72.8%±14.8%) but little change in tumour volume (18.5%±19.0%), the latter result corresponding to that in the early-recurrence group. Using tumour volume only, the no-recurrence group was differentiated from both the early- and the late-recurrence group (P < 0.01), but the early-recurrence group was not differentiated from the late-recurrence group. Using the MET uptake data, the early-recurrence group was clearly distinguished from the late-recurrence group (P<0.01), but the late-recurrence group was indistinguishable from the no-recurrence group. CT was useful in distinguishing the no-recurrence group from the groups in which there was ultimate recurrence, whether early or late. When a residual mass is seen on CT, PET seems to be helpful in evaluating tumour viability.

Studies on 18F-labeled pyrimidines. Tumor uptakes of 18F-5-fluorouracil, 18F-5-fluorouridine, and 18F-5-fluorodeoxyuridine in animals

Three 18F-labeled pyrimidines, 18F-5-fluorouridine (18F-5-FUR), 18F-5-fluorouracil (18F-5-FU), and 18F-5-fluorodeoxyuridine (18F-5-FdUR), were examined regarding tissue distribution and tumor uptake in ascitic hepatoma AH109A-bearing rats. The differential absorption ratios of tumors of 18F-5-FUR, 18F-5-FU, and 18F-5-FdUR were 0.75±0.21, 0.92±0.15, and 0.96±0.24 at 30 min, and 0.37±0.09, 0.64±0.34, and 0.60±0.17 at 120 min, respectively. The tumor-to-organ ratios obtained with three radiopharmaceuticals, especially with blood, heart, lung, muscle, and brain were high and these ratios increased with time. The tumor-to-organ ratios obtained with 18F-5-FdUR were always 1.3–4 times higher than 18F-5-FU and 18F-5-FUR. We concluded that 18F-5-FdUR was a suitable radiopharmaceutical for tumor imaging. Positron emission tomography of a rabbit tumor located on the chest with 18F-5-FdUR clearly showed the tumor within 1 h.

Adenosine A1 Receptors in the Central Nervous System: Their Functions in Health and Disease, and Possible Elucidation by PET Imaging

Adenosine is a neuromodulator with several functions in the central nervous system (CNS), such as inhibition of neuronal activity in many signaling pathways. Most of the sedating, anxiolytic, seizure-inhibiting and protective actions of adenosine are mediated by adenosine A(1) receptors (A(1)R) on the surface of neurons and glia. Positron Emission Tomography (PET) is a powerful in vivo imaging tool which can be applied to investigate the physiologic and pathologic roles of A(1)R in the human brain, and to elucidate the mechanism of action of therapeutic drugs targeting adenosine receptors, nucleoside transporters and adenosine-degrading enzymes. In this review article, we discuss (i) functions of adenosine and its receptors in cerebral metabolism; (ii) radioligands for A(1)R imaging: xanthine antagonists, non-xanthine antagonists, and agonists; (iii) roles of A(1)R in health and disease, viz. sleep-wake regulation, modulation of memory retention and retrieval, mediating the effects of alcohol consumption, protecting neurons during ischemia and reperfusion, suppression of seizures, modulating neuroinflammation and limiting brain damage in neurodegenerative disorders. The application of PET imaging could lead to novel insights in these areas. Finally (iv), we discuss the application of PET in pharmacodynamic studies and we examine therapeutic applications of adenosine kinase inhibitors, e.g. in the treatment of pain, inflammation, and epilepsy.

Differential diagnosis of AH109A tumor and inflammation by radioscintigraphy with L-[methyl-11C]methionine.

For the evaluation of tumor imaging with l‐[methyl‐11C]methionine (11C‐Met), a basic study on the differentiation of tumor from inflammation with 11C‐Met and a comparison of the diagnostic value of the image with that obtained using 67Ga citrate, a conventional scintigraphic agent, are important. 11C‐Met accumulations into inflammatory lesions, AH109A tumor and normal tissues of rats were examined by means of a tissue distribution study. Aseptic inflammatory lesions on the back of Donryu rats induced by croton oil and 1.5% carrageenan showed significantly lower accumulations of 11C‐Met than the AH109A tumor. Histologically, croton oil induced granulomatous inflammation and carrageenan, acute exudative inflammation. Whole‐body antoradiography with l4C‐Met, a substitute for 11C‐Met, was negative in the carrageenan lesion and showed a slightly increased activity at the periphery of the croton oil lesion, in contrast with the high tumor activity. Whole‐body autoradiogra‐phy with 67Ga citrate was performed to compare the imaging ability with that of 14C‐Met; it showed high activities in the tumor, bone, and intestine, and a broad increased activity at the periphery of the croton oil lesion, but was negative in the carrageenan lesion. 11C‐Met accumulations in the inflammations were very low and clinical application with positron emission tomography, should be useful for the differential diagnosis of tumor from inflammation.

Studies on 18F-labeled pyrimidines III. Biochemical investigation of 18F-labeled pyrimidines and comparison with 3H-deoxythymidine in tumor-bearing rats and mice

Metabolic studies of 18F-labeled 5-fluoro-2′-deoxyuridine (FdUrd), 5-fluorouridine(FUrd) and 5-fluorouracil (FUra) were performed in tumor-bearing rats and mice. Also, the usefulness of 18F-FdUrd and 3H-deoxythymidine (dThd) for tumor detection was compared. In the tumor, 2 h after the injection of the 18F-pyrimidines, 3%–11% and 6%–14% of the 18F was present in the nuclear and microsomal fractions, respectively, and 17%–34% and 19%–24% of the 18F was incorporated into the acid-insoluble and nucleotide fractions, respectively. Of the three 18F-pyrimidines, 18F-FUrd demonstrated the highest incorporation rate, while 18F-FUra showed the lowest incorporation rate. The incorporation in the spleen, small intestine, and liver was less than that in the tumor. 3H-dThd and 18F-FdUrd were injected into the same mice. The 3H-dThd was accumulated in the spleen, small intestine, and tumor, and in these three tissues significant amounts of the 3H were incorporated into acid-insoluble materials. However, the clearance of 18F-FdUrd was slow in the tumor but rapid in the spleen and small intestine. In the autoradiograms of the tumor, 18F and 3H showed a slightly different distribution. Both distribution patterns were unchanged when the soluble materials were rinsed out with perchloric acid. For tumor detection, 18F-FdUrd gives the same information as radio-dThd, and further information can be obtained by positron-emission tomography.

Metabolic fate of L-[methyl-11C] methionine in human plasma

The metabolites of L-[methyl-11C]methionine in the plasma of 8 patients with tumor were measured for 60 min after injection. In the plasma, after a rapid clearance, the total radioactivity remained constant, and protein-bound radioactivity increased rapidly. Non protein metabolites detected by HPLC as at least two components besides methionine, increased with time. Significant individual variations for the metabolism were observed. AT 60 min after injection, 36.5% (range: 16%–72%) and 45.3% (range: 13%–74%) of the 11C was measured as methionine and labeled proteins, respectively.

Comparative study of specific activity of [11C]methyl iodide: A search for the source of carrier carbon

Abstract Any no-carrier-added 11 C-compounds prepared from [ 11 C]CH 3 I seem to coexist with at least about 0.2 μmol of its non-radioactive form (carrier). In order to elucidate the source of the carrier, 11 C]CH 3 I prepared under various conditions was converted into several 11 C-compounds and their specific activities were measured by high performance liquid chromatography. Carbon contamination of LiAlH 4 was also examined by gas chromatography. It was shown that only a negligible amount of CO 2 was brought with the irradiated target N 2 gas and that the carrier amount decreased remarkably with the reduction of the amount and concentration of the LiAlH 4 THF solution but not to less than 0.2 μmol. The use of Et 2 O or Pr 2 O instead of THF was found to give EtOH or PrOH, respectively, together with MeOH, all in small amounts. Hence, the 0.2 μmol carrier can be regarded as being originated in MeOH formed from a trace of THF remaining in the LiALH 4 after its drying step.