Fully automated synthesis of [18F]fluoromisonidazole using a conventional [18F]FDG module

We developed a new fully automated method for the synthesis of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) by modifying a commercial FDG synthesizer and its disposable fluid pathway. A three-step procedure was used to prepare the tosylate precursor, 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydrofuranyl-3-O-toluenesulfonylpropanediol. Using glycerol as the starting material, the precursor was synthesized with a yield of 21%. The optimal labeling conditions for the automated synthesis of [¹⁸F]FMISO was 10 mg of precursor in acetonitrile (2 ml heated at 105°C for 360 s, followed by heating at 75°C for 280 s and hydrolysis with 1 N HCl at 105°C for 300 s. Using 3.7 GBq of [¹⁸F]F⁻ as a starting activity, [¹⁸F]FMISO was obtained with high end-of-synthesis (EOS) radiochemical yields of 58.5±3.5% for 60.0±5.2 min with high-performance liquid chromatography (HPLC) purification. When solid-phase purification steps were added, the EOS radiochemical yields were 54.5±2.8% (337±25 GBq/μmol) for 70.0±3.8 min (n=10 for each group, decay-corrected). With a high starting radioactivity of 37.0 GBq, we obtained radiochemical yields of 54.4±2.9% and 52.8±4.2%, respectively (n=3). The solid-phase purification removed unreacted [¹⁸F]fluoride and polar impurities before the HPLC procedure. Long-term tests showed a good stability of 98.2±1.5%. This new automated synthesis procedure combines high and reproducible yields with the advantage of using a disposable cassette system.     

Preparation of the hypoxia imaging PET tracer [F]FAZA: reaction parameters and automation

¹⁸F-labeling of the nitroimidazole nucleoside analogue 1-(5-fluoro-5-deoxy--D-arabinofuranosyl)-2-nitroimidazole (FAZA) was developed to use this tracer in PET for detection of hypoxia. Parameters for labeling and hydrolysis were optimized with regard to amount of precursor, temperature and time. Labeling yields reached a maximum of 62±4% at 100 °C within 5 min using 5 mg of precursor. Hydrolysis was best performed with 1 mL of 0.1 N NaOH at 20 °C for 2 min. Transfer of these conditions to an automated synthesizer resulted in an overall radiochemical yield of 20.7±3.5%. Absolute yields at EOS were 9.8±2.3 GBq of [¹⁸F]FAZA ready for injection (n=21; 50 min after EOB; irradiation parameters: 35 μA, 60 min). Thus, a convenient approach suitable for large-scale production of [¹⁸F]FAZA was developed by an automated process.     

Synthesis of a F-18 labeled analog of antitumor prostaglandin Δ-pGA1 methyl ester using p-[F]Fluorobenzylamine

A fluorine-18 labeled analog of an antitumor prostaglandin Δ⁷-PGA₁ methyl ester, 15-deoxy-13,14-dihydro-Δ⁷-PGA₁ 4-[¹⁸F]fluorobenzyl amide ([¹⁸F]3), was synthesized as a tracer candidate for detecting tumors with positron emission tomography. p-[¹⁸F]Fluorobenzylamine (p-[¹⁸F]FBnA) used as a labeled precursor for the synthesis of [¹⁸F]3 was prepared by fluorination of a 4-N, N, N-trimethylammoniumbenzonitrile triflate with [¹⁸F]fluoride and subsequent reduction with borane-dimethylsulfide. Radiochemical yield and purity of p-[¹⁸F]FBnA obtained were 39–49% (decay uncorrected) and 91–96%, respectively, after C18 Sep-Pak purification. Treatment of p-[¹⁸F]FBnA with a 15-deoxy-13,14-dihydro-Δ⁷-PGA₁ N-succinimidyl ester in acetonitrile and subsequent HPLC purification gave radiochemically pure (>99%) [¹⁸F]3 with a 58% decay uncorrected yield. The total synthesis time was 70 min from the start of the radiosynthesis of p-[¹⁸F]FBnA.     

Efficient synthesis of 2-bromo-1-[F]fluoroethane and its application in the automated preparation of F-fluoroethylated compounds

An efficient synthesis of 2-bromo-1-[¹⁸F]fluoroethane from commercially available 1,2-dibromoethane and its integration into an automated preparation device was developed for the routine synthesis of ¹⁸F-fluoroethylated compounds. The 1,2-dibromoethane was reacted with the [¹⁸F]fluoride/Kryptofix^®2.2.2./carbonate complex in acetonitrile at 70°C for 3 min resulting in 60–70% radiochemical yields. The crude reaction mixture was diluted with water, loaded on a LiChrolute^®EN-cartridge, eluted with acetonitrile and passed through an AluminaB^®-cartridge. This method provides 2-bromo-1-[¹⁸F]fluoroethane with 98% radiochemical purity and <0.1 μmol of 1,2-dibromoethane within 10 min, thus avoiding a purifying distillation step. This method was easily integrated into an automated system for the routine synthesis of ¹⁸F-fluoroethylated compounds.     

Synthesis of the I- and I-labeled cholinergic nerve marker (-)-5-iodobenzovesamicol

The highly toxic curaremimetic and cholinergic neuron marker (−)-5-iodobenzovesamicol (IBVM) has been labeled with iodine-125 and iodine-123. [¹²⁵I]IBVM, suitable for animal distribution and ex vivo autoradiographic studies, was synthesized by solid-state exchange; isolated yields were 65–89% with specific activities in the range of 130–200 Ci/mmol. The synthesis of no-carrier-added (−)-5-[¹²⁵I]IBVM from the corresponding chiral (−)-5-(tri-n-butyltin) derivative using Na¹²⁵I was evaluated using the oxidants H₂O₂, peracetic acid and chloramine-T. Both peracetic acid and chloramine-T gave good yields (70–95%). However, when Na¹²³I was utilized, acceptable yields of [¹²³I]IBVM were obtained only with chloramine-T. Use of the latter oxidant did produce 5-chlorobenzovesamicol which was eliminated during HPLC purification. After optimization of the reaction parameters, [¹²³I]IBVM in batch sizes of 10–27 mCi, is routinely obtained with a specific activity of 30–70,000 Ci/mmol, radiochemical purity (>97%) and chiral purity (>98%). Isolated radiochemical yields have averaged 71% (N = 40). Distribution analyses of [¹²⁵I]IBVM and [¹²³I]IBVM in mice 4 h following intravenous administration show essentially equivalent concentrations of the two tracers in the four brain regions sampled. The exceptionally high specific activity of [¹²³I]IBVM has made possible the evaluation of this radiotracer in humans.     

Synthesis of [18F]Xeloda as a novel potential PET radiotracer for imaging enzymes in cancers

Xeloda (Capecitabine), a prodrug of antitumor agent 5-fluorouracil, is the first and only oral fluoropyrimidine to be approved for use as second-line therapy in metastatic breast cancer, colorectal cancer, and other solid malignancies. Fluorine-18 labeled Xeloda may serve as a novel radiotracer for positron emission tomography (PET) to image enzymes such as thymidine phosphorylase and uridine phosphorylase in cancers. The precursor 2′,3′-di-O-acetyl-5′-deoxy-5-nitro-N⁴-(pentyloxycarbonyl)cytidine (11) was synthesized from D-ribose and cytosine in 8 steps with approximately 18% overall chemical yield. The reference standard 5′-deoxy-5-fluoro-N⁴-(pentyloxycarbonyl)cytidine (Xeloda; 1) was synthesized from D-ribose and 5-fluorocytosine in eight steps with approximately 28% overall chemical yield. The target radiotracer 5′-deoxy-5-[¹⁸F]fluoro-N⁴-(pentyloxycarbonyl)cytidine ([¹⁸F]Xeloda; [¹⁸F]1) was prepared by nucleophilic substitution of the nitro-precursor with K¹⁸F/Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with the HPLC method in 20–30% radiochemical yields.     

Radiosynthesis and ex vivo evaluation of [11C]-SIB-1553A as a PET radiotracer for beta4 selective subtype nicotinic acetylcholine receptor

[¹¹C]-SIB-1553A ((±)-4-[2-((N-[¹¹C]-methyl)-2-pyrrolidinyl)ethyl]thiophenol) was labelled with carbon-11 (t_1/2=20.4 min) and evaluated in vivo as potential radiotracer for noninvasive assessment of the β4 subunit nicotinic acetylcholine neurotransmission system with positron emission tomography (PET). The labelling precursor was obtained within five steps from N-Boc-prolinal in 45–56% overall yields. The radiosynthesis of [¹¹C]-SIB-1553A was achieved by a selective N-[¹¹C]-methylation in 32 min with a radiochemical purity greater than 97%, 7.5–30 GBq/μmol of specific radioactivity and 55–65% radiochemical yield (decay corrected, based on [¹¹C]methyl iodide). The ex vivo pharmacological profile of [¹¹C]-SIB-1553A was evaluated in rats with biodistribution studies in organs and in brain structures by autoradiography. The radiotracer uptake in the brain reached 0.49 %ID/g at 10 min and no brain radiometabolite was detected 40 min after intravenous injection. The quantification of radioactivity in various cerebral structures indicated a significantly higher radioactivity level at 15 min than at 30 min. Among the β4 nAChR subunit-rich structures studied in the rat brain, only the thalamus at 15 and 30 min and the hippocampus at 30 min showed significantly higher uptake. Moreover, competition studies performed with SIB-1553A (15 min before the radiotracer injection) revealed only a low specific binding estimated to 7% of the total binding at 15 min and 13% at 30 min.     

Fluorine-18 and carbon-11 labeled amphetamine analogs—Synthesis, distribution, binding characteristics in mice and rats and a PET study in monkey

No-carrier-added (NCA) (±)-p-[¹⁸F]fluoroamphetamine (2a) and (±)-6-[¹⁸F]fluoro-3,4-methylene-dioxyamphetamine (2b) were synthesized through a multistep synthesis by nucleophilic substitution of the appropriate precursors (p-nitrobenzaldehyde, 1a and 6-nitropiperonal 1b, respectively) with [¹⁸F]fluoride followed by condensation with nitroethane and reduction with LAH in 20–30% yield (EOB) in a synthesis time of 90–109 min from EOB. NCA (−)-[¹¹C]methamphetamine (4a) and (±)-3,4-methylenedioxy-N-[¹¹C]methamphetamine (4b) were synthesized by methylation of the appropriate desmethyl precursors 3a and 3b with [¹¹C]H₃I in 40–60% yield (EOB) in a synthesis time of 30 min from EOB. Animal studies in mouse and rat revealed that the relative tissue uptake of these radiotracers was kidneys > lungs > liver > spleen > brain > heart > blood. The uptakes of these radiotracers in mouse brain were high and similar at 5 min post-injection (approx. 5%/g) but radioactivity then declined rapidly (approx. 1%/g at 60 min post-injection). For compounds 2a and 2b, the activity in the femur did not increase with time indicating in vivo defluorination may not be the major route of metabolism. Monoamine uptake inhibitors (nomifensine, fluoxetine and nisoxetine) did not inhibit but enhance the uptake of (−)-[¹¹C]methamphetamine (4a) in the rat brain by greater than 50%. A PET study in a Rhesus monkey revealed that the uptakes of (−)-[¹¹C]methamphetamine in different brain regions were similar and the retention of the radioactivity in these regions remained constant throughout the study. Analysis of arterial plasma by HPLC showed that 50% of radioactivity remained as 4a at 60 min post-injection.     

Synthesis and evaluation of N,N-dimethyl-2-(2-amino-5-[F]fluorophenylthio)benzylamine (5-[F]-ADAM) as a serotonin transporter imaging agent

The synthesis and evaluation of a new serotonin transporter (SERT) imaging agent, N,N-dimethyl-2-(2-amino-5-[¹⁸F]fluorophenylthio)benzylamine (5-[¹⁸F]-ADAM) is reported. Nucleophilic substitution of N,N-dimethyl-2-(2-nitro-5-bromophenylthio)benzylamine with K[¹⁸F]/Kryptofix 2.2.2 in DMSO at 125°C followed by reduction with NaBH₄–Cu(OAc)₂ in EtOH at 78°C and purification with HPLC produces the desired compound with an unoptimized yield of 5–10% in a synthesis time of 150 min from EOB. The biodistribution of 5-[¹⁸F]-ADAM in rats showed a high initial uptake and relatively rapid clearance in the brain (3.221±0.762, 0.440±0.059, 0.160±0.035 and 0.028±0.003% injected dose/organ at 2, 30, 60 and 120 min after I.V. injection, respectively) with the specific binding peaking at 1 h postinjection (hypothalamus/cerebellum and hippocampus/cerebellum were 2.97 and 3.59, respectively). The initial uptake in blood, lung, kidney and heart were also high, but it cleared rapidly. The radioactivity in the femur increased with time for 5-[¹⁸F]-ADAM indicating that in vivo defluorination may occur. Metabolism studies in rats showed that 5-[¹⁸F]-ADAM was not metabolized in rat brain, but was metabolized rapidly in the blood. Blocking experiments showed that there were significant decreases in the uptake of 5-[¹⁸F]-ADAM in the brain regions (hypothalamus, hippocampus and striatum) where SERT concentrations are high when rats were pretreated with (+)McN 5652 (2 mg/kg, 5 min prior to IV injection of 5-[¹⁸F]-ADAM). These results suggest that 5-[¹⁸F]-ADAM may be a potential new serotonin transporter PET imaging agent. However, due to its rapid wash-out from the brain, defluorination in vivo and lower uptake in the brain than 4-[¹⁸F]-ADAM, 5-[¹⁸F]-ADAM may not be as useful as 4-[¹⁸F]-ADAM as a SERT imaging agent.     

Synthesis and biological evaluation of 1-(4-[18F]fluorobenzyl)-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine for in vivo studies of acetylcholinesterase

We synthesized and evaluated 1-(4-fluorobenzyl)-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (4-FDP), which is an analog of donepezil. The 4-[¹⁸F]FDP was prepared by reductive alkylation of debenzylated donepezil with 4-[¹⁸F]fluorobenzaldehyde in high radiochemical yield (decay-corrected, 40–52%) and with high effective specific activity (30–38 GBq/μmol). Tissue distribution studies in mice demonstrated nonspecific distribution of the 4-[¹⁸F]FDP in brain regions, suggesting that this radioligand may not be a suitable agent for in vivo studies of acetylcholinesterase (AChE), despite its potent in vitro biological activity.     

Highly efficient automated synthesis of [C]choline for multi dose utilization

[¹¹C]Choline has been under investigation as a PET ligand for imaging tumor tissue, especially prostate cancer. An improved, automated synthesis of the tracer now was established. [¹¹C] Choline was produced by labeling 2-(dimethylamino)-ethanol (DMAE) with [¹¹C]CH₃I in a Tefzel^® tube at room temperature without solvent. The product was purified using a cation exchange cartridge. Reaction conditions were optimized with respect to synthesis time and amount of DMAE, resulting in radiochemical yields higher than 80% using 60 μl of DMAE in 20 min, radiochemical purity was >99% and residual DMAE was below 10 ppm. After ¹¹C-production of 1 h at 50 μA [¹¹C]choline activities of 30.0±5.6 GBq (n=29) were obtained in sterile solution ready for intravenous administration.     

F-labeling and biodistribution of the novel fluoro-quinolone antimicrobial agent, trovafloxacin (CP 99,219)

[¹⁸F]CP 99,219 [(1,5,6)-7-(6-amino-3-azabicyclo [3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid] was prepared by ¹⁸F for ¹⁹F exchange followed by reverse-phase HPLC purification. Studies of the effects of reaction time and temperature on ¹⁸F incorporation demonstrated that heating 1.0 mg of CP 99,219 in 0.5 cc of DMSO with 4.5 mg of K₂CO₃ and 24 mg of Kryptofix for 15 min at 160 °C results in the optimal compromise between radiochemical yield and purity. This method routinely provides radiochemical yields of 15–30% [EOS] with radiochemical purities of >97%. Varying the concentration of CP 99,219 in the reaction mixture had no effect on yield. Biodistribution studies in rats demonstrated that significant concentrations of drug accumulate in most tissues. The tissues with the highest concentrations of drug were intestine, liver, kidney, and stomach.     

High yield synthesis of high specific activity R-(−)-[C]epinephrine for routine PET studies in humans

R-(−)-[¹¹C]Epinephrine ([¹¹C]EPI) has been synthesized from R-(−)-norepinephrine by direct methylation with [¹¹C]methyl iodide or [¹¹C]methyl triflate. The total synthesis time including HPLC purification was 35–40 min. The radiochemical yields (EOB) were 5–10% for [¹¹C]methyl iodide and 15–25% for [¹¹C]methyl triflate. Radiochemical purity was >98%; optical purity determined by radio-chiral HPLC was >97%. The [¹¹C]methyl triflate technique produces R-(−)-[¹¹C]epinephrine in quantities (80–170 mCi) sufficient for multiple positron emission tomography studies in humans. The two synthetic methods are generally applicable to the production of other N-[¹¹C]methyl phenolamines and N-[¹¹C]methyl catecholamines.     

Improved target system for production of high purity [F]fluorine via the O(p,n)F reaction

An improved aluminium target system for production of elemental fluorine via the ¹⁸O(p,n)¹⁸F reaction using a two-step irradiation protocol is described. In the first step highly enriched gaseous oxygen-18 is irradiated with protons to form fluorine-18 which gets deposited on the inner target surface. In the second step, after cryogenic recovery of oxygen-18 target gas, a mixture of elemental ‘cold’ fluorine and krypton is introduced and a short proton irradiation is done, whereby an isotopic exchange between the gaseous fluorine and the deposited radiofluorine occurs. The second step leads to the recovery of the radiofluorine as [¹⁸F]fluorine. Optimisation studies were performed regarding the yield and specific radioactivity of [¹⁸F]fluorine. Furthermore, some irradiation parameters relevant to the recovery step were investigated. It was found that a 15 to 20 min irradiation with a beam current of 20 μA is sufficient for the isotopic exchange between the fluorine-carrier and the ¹⁸F-radioactivity deposited on the inner wall of the target. The distribution of the ¹⁸F-radioactivity deposited on the inner target surface is inhomogeneous, probably due to convection effects. Extensive radioanalytical techniques were applied to characterise the reactivity of [¹⁸F]fluorine and to identify undesired nonreactive ¹⁸F-compounds, mainly [¹⁸F]tetrafluoromethane and [¹⁸F]nitrogentrifluoride. The [¹⁸F]fluorine produced in the system used has the distinction of having a negligible contamination from those inert ¹⁸F-compounds. This is a combined effect of the use of highest purity gases and a welded target construction, which avoids any contact of the gases with organic material during irradiations. The target has proved to be very reliable for production of [¹⁸F]fluorine in high yields of up to 34 GBq and specific activities of 350–600 GBq/mmol, both at 30 min after end of activation bombardment.     

Dependency of the [18F]fluoromisonidazole uptake on oxygen delivery and tissue oxygenation in the porcine liver

We have previously shown that the accumulation of fluorine-18-labeled fluoromisonidazole ([¹⁸F]FMISO) is inversely correlated to tissue oxygenation, allowing the quantification of porcine liver tissue hypoxia in vivo. We determined the activity from administered [¹⁸F]FMISO in relation to the hepatic oxygen availability and the partial pressure of oxygen in tissue (tPO₂) to define a critical oxygen delivery on a regional basis. [¹⁸F]FMISO was injected 2 h after onset of regional liver hypoxia due to arterial occlusion of branches of the hepatic artery in 10 domestic pigs. During the experimental procedure the fractional concentration of inspired oxygen (FiO₂) was set to 0.67 in group A ( N=5) and to 0.21 in group B ( N=5) animals. Immediately before sacrifice, the tPO₂ was determined in normal flow and flow-impaired liver segments. The standardized uptake values (SUV) for [¹⁸F]FMISO was calculated from 659 single tissue samples obtained 3 h after injection of approximately 10 MBq/kg body weight [¹⁸F]FMISO and was compared with the regional total hepatic oxygen delivery (DO₂) calculated from the regional arterial and portal venous flow (based on ¹⁴¹Ce- and ^99mTc-microspheres measurements) and the oxygen content of the arterial and portal venous blood. In 121 tPO₂-measured liver tissue samples, the mean DO₂ was significantly decreased in occluded liver tissue samples [group A: 0.063 (0.044–0.089); group B: 0.046 (0.032–0.066)] compared to normal flow segments [group A: 0.177 (0.124–0.252); group B: 0.179 (0.128–0.25) mL·min⁻¹·g⁻¹; geometric mean (95% confidence limits); p < 0.01 in group A and p < 0.001 in group B]. The tPO₂ of occluded segments [group A: 5.1 (3.2–8.1); group B: 3.9 (2.4–6.2) mm Hg] was significantly decreased compared to normal flow segments [group A: 20.2 (12.6–32.5); group B: 22.4 (14.3–35.2) mm Hg; p < 0.01 in group A and p < 0.001 in group B]. Three hours after [¹⁸F]FMISO administration, the mean [¹⁸F]FMISO SUV determined in tPO₂-measured occluded segments was significantly higher [group A: 4.08 (3.12–5.34), group B: 5.43 (4.14–7.13)] compared to normal liver tissue [group A: 1.57 (1.2–2.06), group B: 1.5 (1.16–1.93); p < 0.001 for both groups]. The [¹⁸F]FMISO SUV allowed prediction of the tPO₂ with satisfying accuracy in hypoxic regions using the exponential regression curve { [¹⁸F]FMISO=1.05+6.7^{(−0.117 tPO₂}); r²=0.75;p < 0.001}. In addition, regardless of ventilation conditions, a significant exponential relationship between the DO₂ and the [¹⁸F]FMISO SUV was found ( r²=0.39,p < 0.001). Our results suggest that the reduction of the oxygen delivery below the critical range of 0.1–0.11 mL·min⁻¹·g⁻¹ regularly causes liver tissue hypoxia. The severity of hypoxia is reflected by the [¹⁸F]FMISO accumulation and allows the in vivo estimation of the tPO₂ in hypoxic regions.     

Recovery of F from [O] water by electrochemical method

An electrochemical method for producing ¹⁸F sources for the slow positron beam was applied to the recovery of ¹⁸F from H₂¹⁸O water. The ¹⁸F of activities 150–227 mCi (5.55–8.40 GBq) was electro-deposited on a graphite rod and then emitted into pure water. The best result of the efficiency for the electro-deposition for 5 min was 97% and that for the electro-emission for 5 min was 89%. The H₂¹⁸O water is expected to be reused much more easily by this method than by the ion exchange resin method. The metal impurities contained in the ¹⁸F solution were considerably reduced by using this method.     

Highly potent indanamine serotonin uptake blockers as radiotracers for imaging serotonin uptake sites

Two highly potent indanamine serotonin (5-HT) uptake blockers, trans-3′-(4′-bromophenyl)-1-indanamine (trans-[¹¹C]DBPI or [¹¹C]Lu 19-056) and its iodo analog, trans-3′(4′-[¹²⁵I]iodophenyl)-1-indanamine (trans-[¹²⁵I]DIPI) were evaluated as radiotracers for imaging 5-HT uptake sites in vivo. Trans-[¹¹C]DBPI was synthesized by N-methylation of the normethyl precursor with [¹¹C]iodomethane. Trans-[¹²⁵I]DIPI was synthesized by iododestannylation of the tributyltin precursor with [¹²⁵I]NaI. Radiochemical yields for the [¹¹C] and [¹²⁵I] radiotracers were 34 and 40%, with specific activities of 4000 and 1800 mCi/μmol, respectively. In vitro, the iodo analog, trans-DIPI, showed an IC₅₀ value of 0.26 nM in inhibition of [³H]paroxetine binding to 5-HT uptake sites in rat cortex. The potency was found to be equivalent to that of paroxetine or McN5652. In vivo, after i.v. injection into mice, both radiotracers showed high uptake in brain (3–4% dose/whole brain at 15 min) and high accumulation into target tissues such as hypothalamus and olfactory tubercles (7–8% dose/g at 60 min). The binding was blocked by pre-injection of 5 mg/kg of paroxetine. While the in vivo distribution agreed with previously reported 5-HT uptake site distribution, the radiotracers showed high uptake in non-target tissues such as cerebellum, resulting in low target-to-non-target ratios (1.5–1.6 at 60 min). Since washout from non-target regions was slower than from target regions, longer-time observation with ¹²⁵I up to 6 h did not improve the ratios. HPLC analyses of mouse brain homogenates and blocking studies indicated that the high uptake in non-target regions is not the result of metabolism or any interaction of the radiotracers with those tissues via specific binding sites. In spite of low target-to-non-target ratios, target regions with high density of 5-HT uptake sites, such as the raphe nuclei, superior colliculi and substantia nigra, were visualized with trans-[¹²⁵I]DIPI by ex vivo autoradiography, since the radiotracer showed high specific binding (total minus nonspecific binding).     

Synthesis of C-labeled desipramine and its metabolite 2-hydroxydesipramine: Potential radiotracers for pet studies of the norepinephrine transporter

The antidepressant desipramine (DMI) and its principal metabolite 2-hydroxydesipramine (HDMI) have been radiolabeled with ¹¹C for PET studies. The normethyl precursors of DMI and HDMI were synthesized from iminodibenzyl in 35% and 11% overall yield, respectively. Direct methylation of the normethyl precursor with [¹¹C]CH₃I, followed by HPLC purification, provided [¹¹C]DMI and [¹¹C]HDMI in 18–30% and 15–23% decay-corrected radiochemical yields, respectively, in a 45 min synthesis time from end of bombardment. The specific activities of the two radiotracers were > 1459 Ci/mmol at the end of synthesis. [¹¹C]DMI and [¹¹C]HDMI have potential utility as PET radiotracers for the norepinephrine transporter.     

Rapid synthesis of [F]FDG without an evaporation step using an ionic liquid

In this study, we describe a new 2-[¹⁸F]fluoro-2-deoxy- -glucose ([¹⁸F]FDG) synthesis without a distillation step. This involves fluorinating in an ionic liquid-containing medium. A test for the effective elution of [¹⁸F]fluoride from the anion exchange resin showed the proper selection of the base and the required eluant composition, which is an essential requirement for the automation of [¹⁸F]FDG synthesis. An ¹⁸F-labeling study by nucleophilic substitution showed that the major factors controlling the yield were the temperature and the reaction medium composition. The ¹⁸F-fluorination proceeded with a labeling efficiency of 74.6±7.4% (n=8) for optimized conditions. Alkaline hydrolysis and purification carried out in the liquid phase provided a final decay-corrected [¹⁸F]FDG yield of 59.1±5.1% (n=3), a radiochemical purity of 91.9±3.7% (n=3), and a reaction time of 13 min. Alkaline hydrolysis and purification carried out in the solid phase provided a final decay-corrected [¹⁸F]FDG yield of 48.8±6.0% (n=3), a radiochemical purity of 96.0±4% (n=3), and a reaction time of 19 min. The rapid and straightforward synthesis of [¹⁸F]FDG can be achieved by eliminating all evaporation steps, which is made possible by the use of ionic liquid-containing media for the fluorination step.     

Imaging of central nAChReceptors with 2-[F]F-A85380: optimized synthesis and in vitro evaluation in Alzheimer''s disease

In vivo labeling of the nicotinic acetylcholine receptors (nAChR) could be a useful tool for early diagnosis of neurodegenerative disorders. 2-[¹⁸F]F-A85380 (2-[¹⁸F]Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine), a ligand with high affinity to the β2 subunit of the nAChRs, has been shown to label neurons in the nAChR-rich thalamus, cortex and striatum in baboons. We report an optimized synthesis resulting in an uncorrected yield of 58% in 45 min (precursor 2), enabling efficient production intended for clinical use. Incubation of normal rat brain sections with 2-[¹⁸F]F-A85380 with subsequent autoradiographic analyses showed the expected distribution in nAChR areas. In human brain sections of Alzheimer's disease (AD) a decrease of 2-[¹⁸F]F-A85380 uptake to 36% of the control group was measured in the thalamus and also in the occipital cortex. These findings suggest that 2-[¹⁸F]F-A85380 is a promising PET-ligand in the diagnosis of AD.