Fluorine-substituted ligands for the peroxisome proliferator-activated receptor gamma (PPARgamma): potential imaging agents for metastatic tumors

The peroxisome proliferator-activated receptor gamma (PPARgamma), a primary regulator of lipid metabolism, is present in many tumor cell lines and animal tumor systems and, in some cases, can mediate effective antitumor therapy with potent synthetic ligands. In an approach to image tumors with positron-emission tomography (PET) based on their content of PPARgamma, we have synthesized two fluorine-substituted analogues of a high affinity ligand from the phenylpropanoic acid class. The analogue having the highest affinity for PPARgamma was labeled with the positron-emitting radionuclide fluorine-18. In tissue distribution studies in normal rats and in SCID mice bearing human breast tumor xenografts, this compound did not show evidence of receptor-mediated uptake. The prospects for using PPARgamma as a target for imaging tumors may be limited by the low receptor concentrations in tumors and by the pharmacokinetic behavior of this class of ligands, which appears to be more favorable for therapy than for imaging.     

Uptake of three [3H]progestins by target tissues in vivo: Implications for the design of diagnostic imaging agents

We have investigated the tissue distribution of radioactivity for 0.5–4 h follwing the i.v. injection of three tritium-labeled progestins in estrogen-primed, immature rats. Whereas [³H]progesterone shows minimal uterine uptake (<0.7% injected dose per gram; %ID/g), the two higher affinity, synthetic progestins [³H]R 5020 (promegestrone) and [³H]ORG 2058 show highly selective uptake that reaches 4–5% ID/g by 1–3 h. The uterus to non-target tissue activity ratio at 2–4 h is approximately 12–20 for R 5020 and ORG 2058, but less than 2 for progesterone; the uterus to blood activity ratio for R 5020 is also high (approximately 15), but is lower for ORG 2058, possibly due to the accumulation of radiolabeled metabolites in the blood. The uterine uptake is selectively blocked by simultaneous injection of a large dose of unlabeled steroid, indicating that the uptake is mediated by a high affinity, low capacity binding system, presumably the progesterone receptor. Pronounced uptake is also observed by the liver and into fat, but is not receptor-mediated. The highly selective target tissue uptake by the two synthetic steroids, but not by progesterone, indicates that one must have ligands with sufficiently high affinity for the target tissue receptor, as well as low affinity for certain non-receptor binding proteins, in order to obtain adequate contrast between target and non-target tissues in dynamic uptake studies. These guidelines will be important in the development of suitable in vivo imaging agents based on the progesterone receptor.     

Biodistribution of N-alkyl and N-fluoroalkyl derivatives of spiroperidol; Radiopharmaceuticals for PET studies of dopamine receptors

There is great interest in the application of positron labeled ligands to map the dopamine receptor in vivo. A series of fluorine-18-labeled N-alkyl and N-fluoroalkyl spiroperidol (SP) derivatives N-methyl[¹⁸F]SP; N-ethyl[¹⁸F]SP; N-(2-[¹⁸F]fluoroethyl)SP; N-propyl[¹⁸F]SP; N-(3-[¹⁸F]fluoropropyl)SP; N-(3-fluoropropyl) [¹⁸F]SP; N-(2-[¹⁸F]fluoropropyl)SP; N-(2-[¹⁸F]fluorobutyl)SP; N-(2-[¹⁸F]fluoropentyl)SP; and N-(2-[¹⁸F]fluorohexyl) SP were synthesized. The lipophilicity of these ligands (log octanol/water partition coefficient) varies from 2.67 to 5.56 and the initial brain uptake in rats, measured at 2 min, was greatest with the methyl, ethyl, propyl, fluoroethyl, and fluoropropyl derivatives. The highest striatum/cerebellum values 1 h after administration were obtained with the N-methyl, N-propyl, and N-3-fluoropropyl derivatives, while that of N-2-fluoroethyl showed the greatest uptake of total activity in the brain at this time. The uptake of all these ligands in the striatum could be blocked by cold SP showing the striatal uptake to be by the dopamine receptors.     

Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A2B receptor

On the basis of a pyrazine core structure, three new adenosine A_2B receptor ligands (7a–c) were synthesized containing a 2-fluoropyridine moiety suitable for ¹⁸F-labeling. Compound 7a was docked into a homology model of the A_2B receptor based on X-ray structures of the related A_2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were determined at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A₁ receptor, 7a was radiolabeled as the most suitable candidate (K_i(A_2B)?=?4.24?nM) in order to perform in vivo studies in mice with the aim to estimate fundamental pharmacokinetic characteristics of the compound class. Organ distribution studies and a single PET study demonstrated brain uptake of [¹⁸F]7a with a standardized uptake value (SUV) of ≈1 at 5?min post injection followed by a fast wash out. Metabolism studies of [¹⁸F]7a in mice revealed the formation of a blood–brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivatives with improved binding properties and metabolic stability in vivo.     

Synthesis and evaluation of new 1-oxa-8-azaspiro[4.5]decane derivatives as candidate radioligands for sigma-1 receptors

We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ₁ receptor ligands. All seven ligands exhibited nanomolar affinity for σ₁ receptors (K_i(σ₁) = 0.47 – 12.1 nM) and moderate selectivity over σ₂ receptors (K_i(σ₂)/ K_i(σ₁) = 2 – 44). Compound 8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [¹⁸F]8 was prepared via nucleophilic ¹⁸F-substitution of the corresponding tosylate precursor, with an overall isolated radiochemical yield of 12–35%, a radiochemical purity of greater than 99%, and molar activity of 94 – 121 GBq/μmol. Biodistribution studies of [¹⁸F]8 in mice demonstrated high initial brain uptake at 2 min. Pretreatment with SA4503 resulted in significantly reduced brain-to-blood ratio (70% − 75% at 30 min). Ex vivo autoradiography in ICR mice demonstrated high accumulation of the radiotracer in σ₁ receptor-rich brain areas. These findings suggest that [¹⁸F]8 could be a lead compound for further structural modifications to develop potential brain imaging agents for σ₁ receptors.     

Radiosynthesis and evaluation of N-(3-[18F]fluoropropyl)paroxetine as a radiotracer for in vivo labeling of serotonin uptake sites by PET

To visualize serotonin uptake sites by positron emission tomography (PET), N-(3-[¹⁸F]fluoropropyl)-paroxetine ([¹⁸F]FPP) (Fig. 1), a derivative of the selective serotonin uptake blocker paroxetine, was synthesized from 3-[¹⁸F]fluoropropyltosylate and paroxetine via a one-pot procedure. The rate of formation of [¹⁸F]FPP was a function of the ratio of the initial amount of paroxetine to that of 1,3-propanediol bistosylate with which [¹⁸F]fluoropropyltosylate was synthesized. When the reaction mixture contained an excess amount of paroxetine over that of the propyl-bistosylate, the radiosynthesis followed by HPLC purification, which took approx. 90 min, gave [¹⁸F]FPP in a radiochemical yield of approx. 8%, and in high radiochemical and chemical purity. The specific activity was 2640 ± 360 mCi/μmol.The brain biodistribution of [¹⁸F]FPP showed no distinguishable localization in regions with high density of serotonin uptake sites such as hypothalamus or olfactory tubercles. In vitro binding assays revealed that N-fluoropropylation of paroxetine reduced the affinity for the serotonin uptake site by three orders of magnitude.     

ZK91587: a novel synthetic antimineralocorticoid displays high affinity for corticosterone (type I) receptors in the rat hippocampus

In vitro cytosol binding assays have shown the properties of binding of a novel steroid, ZK91587 (15 beta, 16 beta-methylene-mexrenone) in the brain of rats. Scatchard and Woolf analyses of the binding data reveal the binding of [3H] ZK91587 to the total hippocampal corticosteroid receptor sites with high affinity (Kd 1.9 nM), and low capacity (Bmax 17.3 fmol/mg protein). When 100-fold excess RU28362 was included simultaneously with [3H] ZK91587, the labelled steroid binds with the same affinity (Kd 1.8 nM) and capacity (Bmax 15.5 fmol/mg protein). Relative binding affinities (RBA) of various steroids for the Type I or Type II corticosteroid receptor in these animals are: Type I: ZK91587 = corticosterone (B) greater than cortisol (F); Type II: B greater than F much greater than ZK91587. In the binding kinetic study, ZK91587 has a high association rate of binding in the rat (20.0 x 10(7) M-1 min-1). The steroid dissociates following a one slope pattern (t 1/2 30 h), indicating, the present data demonstrate that in the rat hippocampus, ZK91587 binds specifically to the Type I (corticosterone-preferring/mineralocorticoid-like) receptor.     

Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide

Translocator protein (TSPO) expression is closely related with neuroinflammation and neuronal damage which might cause several central nervous system diseases. Herein, a series of TSPO ligands (11a–c and 13a–d) with a 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide structure were prepared and evaluated via an in vitro binding assay. Most of the novel ligands exhibited a nano-molar affinity for TSPO, which was better than that of DPA-714. Particularly, 11a exhibited a subnano-molar TSPO binding affinity with suitable lipophilicity for in vivo brain studies. After radiolabeling with fluorine-18, [¹⁸F]11a was used for a dynamic positron emission tomography (PET) study in a rat LPS-induced neuroinflammation model; the inflammatory lesion was clearly visualized with a superior target-to-background ratio compared to [¹⁸F]DPA-714. An immunohistochemical examination of the dissected brains confirmed that the uptake location of [¹⁸F]11a in the PET study was consistent with a positively activated microglia region. This study proved that [¹⁸F]11a could be employed as a potential PET tracer for detecting neuroinflammation and could give possibility for diagnosis of other diseases, such as cancers related with TSPO expression.     

Synthesis and evaluation of a 18F-labeled spirocyclic piperidine derivative as promising σ1 receptor imaging agent

Several spirocyclic piperidine derivatives were designed and synthesized as σ₁ receptor ligands. In vitro competition binding assays showed that the fluoroalkoxy analogues with small substituents possessed high affinity towards σ₁ receptors and subtype selectivity. Particularly for ligand 1′-((6-(2-fluoroethoxy)pyridin-3-yl)methyl)-3H-spiro[2-benzofuran-1,4′-piperidine] (2), high σ₁ receptor affinity (K_i = 2.30 nM) and high σ₁/σ₂ subtype selectivity (142-fold) as well as high σ₁/VAChT selectivity (234-fold) were observed. [¹⁸F]2 was synthesized using an efficient one-pot, two-step reaction method in a home-made automated synthesis module, with an overall isolated radiochemical yield of 8–10%, a radiochemical purity of higher than 99%, and specific activity of 56–78 GBq/μmol. Biodistribution studies of [¹⁸F]2 in ICR mice indicated high initial brain uptake and a relatively fast washout. Administration of haloperidol, compound 1 and different concentrations of SA4503 (3, 5, or 10 μmol/kg) 5 min prior to injection of [¹⁸F]2 significantly decreased the accumulation of radiotracer in organs known to contain σ₁ receptors. Ex vivo autoradiography in Sprague–Dawley rats demonstrated high accumulation of radiotracer in brain areas with high expression of σ₁ receptors. These encouraging results prove that [¹⁸F]2 is a suitable candidate for σ₁ receptor imaging with PET in humans.     

2-Deoxy-2-[18F]fluoro-d-galactose as an In Vivo tracer for imaging galactose metabolism in tumors with positron emission tomography

The feasibility of 2-deoxy-2-[¹⁸F]fluoro-D-galactose ([¹⁸F]FdGal) for imaging galactose metabolism in tumors with positron emission tomography (PET), was investigated using two hepatomas, Yoshida sarcoma, or glioma in rats, and mouse mammary carcinoma. In hepatoma-bearing rats the highest uptake of [¹⁸F]FdGal was observed in the liver followed by the kidney and tumor. The tumor uptake increased with time, and the high uptake ratios of tumor to organ were observed except for the liver and kidney. Tumor uptake was also measured in all tumors. As main metabolites in all tumors, [¹⁸F]FdGal 1-phosphate and UDP-[¹⁸F]FdGal were found by HPLC. Two hepatomas showed a slightly higher uptake and a larger percentage of UDP derivative than the other three tumors. By autoradiography the brain tumor was visualized clearly. These results indicate that [¹⁸F]FdGal has potential as a tracer for imaging galactose metabolism in tumors with PET.     

Corticosteroid receptor analyses in rat and hamster brains reveal species specificity in the type I and type II receptors

In vitro cytosol binding, receptor autoradiography with radiolabelled corticosteroid analogs, and immunocytochemistry with monoclonal antibodies have revealed the presence of two receptor systems for corticosteroids in rat and hamster brains. The type I receptor is found mainly in the hippocampal region, and in the hamster it binds cortisol (F) and corticosterone (B) with similar affinity while in the rat (a species which unlike the hamster secretes solely B) the type I receptor shows high affinity to B and not to F. The type II receptor is more widely distributed in the brain and it binds to F (hamster) or B (rat) with affinity 4-6-fold lower than to the type I. in vivo, the hamster type I and II retain F much more than B while those in the rat show the opposite. In conclusion, the present study clearly indicates species-specificity in type I and type II receptor systems in these animals. Furthermore, the type I receptor displays in vivo stringent preference for retention of the animal's predominantly circulating corticosteroid (F in hamster, in B in rat).     

Synthesis and evaluation of 18F-labeled tertiary benzenesulfonamides for imaging carbonic anhydrase IX expression in tumours with positron emission tomography

Three tertiary benzenesulfonamide inhibitors 4a–c were radiolabeled with ¹⁸F and evaluated for imaging carbonic anhydrase IX (CA IX) expression with positron emission tomography. All three inhibitors exhibit <10 nM affinity for CA IX with no measurable affinity for CA II. Despite good affinity/selectivity to CA IX and excellent stability in plasma, uptake of [¹⁸F]4a–c in CA IX-expressing HT-29 tumours was low without significant contrast. [¹⁸F]4a,b were excreted rapidly, while [¹⁸F]4c exhibited significant in vivo defluorination leading to high bone uptake. Due to minimal uptake in HT-29 tumours compared to normal organs/tissues, ¹⁸F-labeled benzenesulfonamides [¹⁸F]4a–c are not suitable as CA IX imaging agents.     

Synthesis and evaluation of fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives for dopamine D4 receptor imaging

Seven fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were synthesized based on a lead ligand, 3-[[4-(4-iodophenyl)piperazin-1-yl]-methyl]-1H-pyrrolo[2,3-b]pyridine (L-750,667) and evaluated as potential dopamine D(4) receptor imaging agents by positron emission tomography (PET). Binding affinities of these ligands for the dopamine D(2), D(3), and D(4) receptor subtypes were measured in vitro. Most ligands showed high and selective binding for the D(4) receptor. Ligand 7 had high affinity for the D(4) receptor, whereas ligands 1, 2, and 6 showed high selectivity for the D(4) receptor. LogP values were calculated for the ligands in this series and ligand 6 had the lowest lipophilicity. (18)F-labeled ligand 7 demonstrated a uniform regional brain distribution and a rapid washout in mice, probably due to nonspecific binding. Based on their in vitro binding properties and calculated logP values, ligand 6 appears to have the most promise for dopamine D(4) receptor imaging.     

Preparation and biological evaluation of 18F-labeled benzamide analogs as potential dopamine D2 receptor ligands

Three ¹⁸F-labeled benzamide derivatives were prepared and evaluated as potential ligands to study the dopamine D₂ receptor phenomenon. The compounds are analogs of iodobenzamide, eticlopride and raclopride and are labeled with an N-2-[¹⁸F]fluoroethyl functionality on the pyrrolidine ring. The compounds were tested in vitro for binding affinity and found to exhibit somewhat lower affinity than the non-fluorinated analog. In vivo distribution studies revealed that all compounds were more highly bound to plasma proteins than was raclopride. In addition, compartmentation of radioactivity demonstrated nonspecific binding to be the predominate retention in the brain as reflected by the low caudate to cerebellum ratios for these compounds. These three ¹⁸F-labeled benzamide derivatives are inferior to raclopride and iodobenzamide for studies of the D₂ receptor system using positron emission tomography.     

N-(3-[18F]fluoropropyl)-spiperone: The preferred 18F labeled spiperone analog for positron emission tomographic studies of the dopamine receptor

The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spiperone (FSp) and carbon-11 or fluorine-18-labeled N-methyl-spiperone. All three of these ligands have drawbacks in either their chemical preparation or their biological behavior. We have previously prepared a series of N-fluoroalkyl-spiperone derivatives which are simple to prepare in high radiochemical yield. N-[¹⁸F]fluoropropyl-spiperone (3-F-Pr-Sp) and N-[¹⁸F]fluoroethyl-spiperone (2-F-Et-Sp) were the most promising ligands. In vitro competitive binding studies showed affinities for the dopamine receptor of 3-F-Pr-Sp > FSp > 2-F-Et-Sp. Brain extraction studies in a primate model showed that FSp, 2-F-Et-Sp, and 3-F-Pr-Sp were not completely extracted by the brain. High bone uptake and kidney clearance was observed with 3-F-Pr-Sp, while 2-F-Et-Sp cleared through the intestine in rats. This is in contrast to FSp where clearance is through the kidney. Studies to evaluate the extraction of metabolites in the brain were carried out by administering large doses (10 mCi) of FSp, 2-F-Et-Sp and 3-F-Pr-Sp to rats and reinjecting the metabolites in blood into other rats. These experiments showed that < 0.02% of the metabolites from FSp and 3-F-Pr-Sp entered the brain, while 0.5% of the metabolites from 2-F-Et-Sp entered the brain. The majority of the activity present in the cerebellum after the administration of 2-F-Et-Sp is metabolites; therefore 2-F-Et-Sp is unsuitable for PET imaging studies. PET imaging studies in baboons and in one normal human volunteer with 3-F-Pr-Sp showed a high striatum-to-cerbellum ratio, showing that 3-F-Pr-Sp can replace ligands currently in use to study dopamine receptors.     

Place de la tomographie par émission de positons (TEP) au [18F]FDG dans l’exploration des vascularites

[¹⁸F]fluorodeoxyglucose (¹⁸FDG) positron emission tomography (PET) is a noninvasive metabolic imaging modality that is well suited to the assessment of activity and extent of large vessel vasculitis, such as giant cell arteritis and Takayasu arteritis. PET could be more effective than magnetic resonance imaging in detecting the earliest stages of vascular wall inflammation. The visual grading of vascular [¹⁸F]FDG uptake makes it possible to discriminate arteritis from atherosclerosis, providing therefore high specificity. High sensitivity can be achieved provided scanning is performed during active inflammatory phase, preferably before starting corticosteroid treatment. Large scale prospective studies are needed to determine the exact value of PET imaging in assessing the large vessel vasculitis outcome and response to immunosuppressive treatment.     

Ginsenoside RG1 and corticosteroid receptors in rat brain

Old (28 months) male Wistar rats were treated chronically for two weeks with ginsenoside Rg1 or with vehicle delivered via sc implanted Alzet mini-pumps (rate of ginsenoside release 2.4 micrograms/0.5 microliter/h). The number of Type 1 corticosterone-preferring receptor sites (CR) and Type 2 glucocorticoid receptors (GR) was measured in the cytosol of hippocampus tissue of rat brain with an in vitro binding assay. In old rats the Bmax of Type 1 CR and Type 2 GR was reduced by 51.5% and 28.3% respectively. Following the two week treatment with Rg1 the Bmax of Type 1 CR increased by 60% and a receptor concentration was reached which was 21% lower than that observed in the young control animals. Minor differences in affinity of steroid binding to both receptor systems were observed in the groups of rats. The possible binding of ginsenosides to brain corticosteroid receptors in vitro was investigated as well. The inclusion of a 500 fold molar excess of Rg1 in hippocampus cytosol did not displace 3H-corticosterone from its soluble receptor sites. The affinity of Rg1 with these sites in vitro is therefore negligible. In conclusion, the binding capacity of Type 1 CR and Type 2 GR is reduced in the hippocampal brain region of aged rats. Upon chronic infusion of ginsenoside Rg1, only Type 1 CR capacity is restored towards the level observed in young control animals. This finding suggests that in old rats the ginsenoside enhances the CORT signal via Type 1 CR on the function of the hippocampus, which is a limbic brain structure involved in cognition, mood and affect.     

Autoradiographic Localization of the Putative D4 Dopamine Receptor in Rat Brain

The putative dopamine D4 receptor protein in rat brain was labelled and quantified autoradiographically using two selective benzamides: [³H]YM-09151-2 which labels D2, D3 and D4 dopamine receptors and [³H]Raclopride which labels D2 and D3. The difference in densities of both ligands at saturable concentrations, show a regional distribution for the putative D4 receptor in the following rank order: hippocampus > caudate putamen > olfactory tubercle = substancia nigra > nucleus accumbens core > cerebral cortex > cerebellum. A calculated value of 0.34 pmol/mg protein was attributable to D4 receptor maximum capacity in caudate putamen and was obtained after subtracting the Bmax of the ligands. Our results show that the distribution of D4 receptor only partially overlaps with the D4 mRNA localization reported earlier and is not only associated to limbic structures but to motor areas as well.     

Conversion of iodine to fluorine-18 based on iodinated chalcone and evaluation for β-amyloid PET imaging

In the amyloid cascade hypothesis, β-amyloid (Aβ) plaques is one of the major pathological biomarkers in the Alzheimer’s disease (AD) brain. We report the synthesis and evaluation of novel radiofluorinated chalcones, [¹⁸F]4-dimethylamino-4′-fluoro-chalcone ([¹⁸F]DMFC) and [¹⁸F]4′-fluoro-4-methylamino-chalcone ([¹⁸F]FMC), as Aβ imaging probes. The conversion of iodine directly introduced to the chalcone backbone into fluorine was successfully carried out by ¹⁸F-labeling via the corresponding boronate precursors, achieving the direct introduction of fluorine-18 into the chalcone backbone to prepare [¹⁸F]DMFC and [¹⁸F]FMC. In a biodistribution study using normal mice, [¹⁸F]DMFC and [¹⁸F]FMC showed a higher initial uptake (4.43 and 5.47% ID/g at 2?min postinjection, respectively) into and more rapid clearance (0.52 and 0.66% ID/g at 30?min postinjection, respectively) from the brain than a Food and Drug Administration (FDA)-approved Aβ imaging agent ([¹⁸F]Florbetapir), meaning the improvement of the probability of detecting Aβ plaques and the reduction of non-specific binding in the brain. In the in vitro binding studies using aggregates of recombinant Aβ peptides, [¹⁸F]DMFC and [¹⁸F]FMC showed high binding affinity to recombinant Aβ aggregates at the K_d values of 4.47 and 6.50?nM, respectively. In the in vitro autoradiography (ARG) experiment with AD brain sections, [¹⁸F]DMFC and [¹⁸F]FMC markedly accumulated only in a region with abundant Aβ plaques, indicating that they clearly recognized human Aβ plaques in vitro. These encouraging results suggest that [¹⁸F]DMFC and [¹⁸F]FMC may be promising PET probes for the detection of an amyloid pathology and the early diagnosis of AD with marked accuracy.     

Synthesis and evaluation of 6-[1-(2-[(18)F]fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline for positron emission tomography imaging of the metabotropic glutamate receptor type 1 in brain

The purpose of this study was to synthesize 6-[1-(2-[¹⁸F]fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline ([¹⁸F]FPTQ, [¹⁸F]7a) and to evaluate its potential as a positron emission tomography ligand for imaging metabotropic glutamate receptor type 1 (mGluR1) in the rat brain. Compound [¹⁸F]7a was synthesized by [¹⁸F]fluorination of 6-[1-(2-bromo-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline (7b) with potassium [¹⁸F]fluoride. At the end of synthesis, 1280-1830 MBq (n = 8) of [¹⁸F]7a was obtained with >98% radiochemical purity and 118-237 GBq/??mol specific activity using 3300-4000 MBq of [¹⁸F]F⁻. In vitro autoradiography showed that [¹⁸F]7a had high specific binding with mGluR1 in the rat brain. Biodistribution study using a dissection method and small-animal PET showed that [¹⁸F]7a had high uptake in the rat brain. The uptake of radioactivity in the cerebellum was reduced by unlabeled 7a and mGluR1-selective ligand JNJ-16259685 (2), indicating that [¹⁸F]7a had in vivo specific binding with mGluR1. Because of a low amount of radiolabeled metabolite present in the brain, [¹⁸F]7a may have a limiting potential for the in vivo imaging of mGluR1 by PET.