Synthesis of ω-[18F]fluoroalkyl analogs of YM-09151-2 for the measurement of D2-dopamine receptors with PET

Two [¹⁸F]fluoroalkyl analogs of a neuroleptic YM-09151-2 were synthesized via nucleophilic [¹⁸F]fluorination of methanesulfonyloxy- or p-toluenesulfonyloxyalkyl derivatives using no-carrier-added [¹⁸F]fluoride. Although 3-[¹⁸F]fluoropropylaminobenzamide was obtained in good yield, the yield of 2-[¹⁸F]fluoroethyl derivative was severalfold lower. The product, N-[(2RS,3RS)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(3-[¹⁸F]fluoropropyl)-aminobenzamide, was shown to have a striatum-to-cerebellum ratio comparable to that of ¹¹C labeled YM-09151-2 and thus to be a good candidate for measuring D₂-receptors in vivo.     

Rapid reductive-carboxylation of secondary amines,one pot synthesis of N′-(4-11C-methyl)imipramine

A new rapid high yield synthesis of radiolabeled N′-(4-¹¹C-methyl)imipramine has been developed using a reductive-carboxylation approach, in which ¹¹CO₂ is reacted with either N′-trimethylsilyldesimipramine or N′-lithium derivative of desimipramine, followed by lithium aluminum hydride reduction, to give no carrier added or carrier added¹¹C-labeled imipramine respectively. The final product is characterized by chromatographic and spectroscopic methods.     

ω-123I-Hexadecanoic acid metabolic probe of cardiomypathy

The utility of -¹²³I-hexadecanoic acid myocardial scintigraphy as a metabolic probe of cardiomyopathies was investigated. Sixteen patients with a variety of cardiomyopathies and myopathies that involve cardiac muscle and ten volunteers were imaged in the postabsorptive state in a 40° LAO projection after a standard dose of -¹²³I-hexadecanoic acid. An elimination T_1/2 was calculated from the left ventricular myocardial time-activity curve. An uptake index, corrected for chest wall attenuation, was also computed in 7 of 10 volunteers and 8 of 16 patients.Of the 16 patients, only 2 had distinctly abnormal -¹²³I-hexadecanoic acid myocardial tracer kinetics. The first patient had a metabolic disorder of which cartine deficiency was one component. The second patient had endocardial fibroelastosis, a process which has been linked to disorders which deprive the myocardium of oxygen and energy. Therefore, the cardiomyopathy may have been caused by some abnormality of cardiac metabolism other than carnitine deficiency. Although of limited utility in the overall cardiomyopathic population, -¹²³I-hexadecanoic acid myocardial scintigraphy should be further investigated as a screening test for carnitine deficiency and related metabolic abnormalities in patients at risk.Supported by a Canadian Heart Foundation Research FellowshipSupported by an Australian Heart Foundation Travel Grant     

Synthesis of some α-11C-labelled substituted benzyl iodides

The synthesis of the ¹¹C-labelled substituted benzyl iodides 4-methoxy[α-¹¹C]benzyl, 3,4-methylenedioxy[α-¹¹C]benzyl, 3,4-dimethoxy[α-¹¹C]benzyl, 4-chloro[α-¹¹C]benzyl, 4-fluoro[α-¹¹C]benzyl and 4-phenyl[α-¹¹C]benzyl iodides by a batch procedure using liquid extraction is presented. The products were obtained in 25–45% radiochemical yields, decay corrected, and 65–69% radiochemical purities with a total synthesis time of 20–25 min. The potential of these labelled benzyl iodides as precursors in alkylation reactions have been shown. The labelled benzyl iodides were used without further purification in some model reactions using alcoholate as nucleophile.     

Effects of whole-body cryotherapy (-110 °C) on proprioception and indices of muscle damage

The purpose of this study was to investigate the effects of whole-body cryotherapy (WBC) on proprioceptive function, muscle force recovery following eccentric muscle contractions and tympanic temperature (T(TY) ). Thirty-six subjects were randomly assigned to a group receiving two 3-min treatments of -110 ± 3 °C or 15 ± 3 °C. Knee joint position sense (JPS), maximal voluntary isometric contraction (MVIC) of the knee extensors, force proprioception and T(TY) were recorded before, immediately after the exposure and again 15 min later. A convenience sample of 18 subjects also underwent an eccentric exercise protocol on their contralateral left leg 24 h before exposure. MVIC (left knee), peak power output (PPO) during a repeated sprint on a cycle ergometer and muscles soreness were measured pre-, 24, 48 and 72h post-treatment. WBC reduced T(TY) , by 0.3 °C, when compared with the control group (P<0.001). However, JPS, MVIC or force proprioception was not affected. Similarly, WBC did not effect MVIC, PPO or muscle soreness following eccentric exercise. WBC, administered 24 h after eccentric exercise, is ineffective in alleviating muscle soreness or enhancing muscle force recovery. The results of this study also indicate no increased risk of proprioceptive-related injury following WBC.     

Evaluation of the bubble point test of a 0.22-μm membrane filter used for the sterilizing filtration of PET radiopharmaceuticals

Objective

We developed a bubble point test kit and investigated the bubble point test of a 0.22-μm membrane filter used for the sterilizing filtration of [¹⁸F]FDG, [¹¹C]MET and [¹¹C]PIB. The bubble point test of the Millex-GS vented filter was often difficult due to air leakage from the vented portion of this filter. Therefore, to close the vented portion of this filter simply and reliably, we investigated the use of various materials.

Methods

The bubble point test of the Millex-GS vented filter was performed by closing the vented portion of this filter with various materials, such as vinyl tape, plastic paraffin film (parafilm), urethane elastomer adhesive mat and polyethylene foam cushion tape. Gradually, the plunger inside a syringe filled with air was pushed down to increase the pressure on the pressure gauge and the bubble point test kit. Simultaneously, the pressure when a continuous stream of air bubbles that appeared out of the 0.22-μm membrane filter was measured as the product-wetted bubble point value. Then, the plunger inside a syringe filled with 10 mL of water was pushed down to wash the 0.22-μm membrane filter. As in the case in the above-mentioned method of measuring the product-wetted bubble point, the water-wetted bubble point value was measured.

Results

The use of the polyethylene foam cushion tape and a double clip could easily and reliably prevent air leakage from the vented portion of the Millex-GS vented filter. In the bubble point test of [¹⁸F]FDG, [¹¹C]MET and [¹¹C]PIB, the product-wetted bubble point values were 382.7 ± 6.9 kPa, 385.4 ± 6.2 kPa and 351.6 ± 7.6 kPa, respectively. The bubble point ratio was used to determine the minimum product-wetted bubble point value. All results of the product-wetted bubble point test were beyond the minimum product-wetted bubble point value (334.4 kPa ([¹⁸F]FDG), 334.4 kPa ([¹¹C]MET) and 310.3 kPa ([¹¹C]PIB)). Then, the water-wetted bubble point values were 396.5 ± 8.3 kPa, 395.8 ± 8.3 kPa and 390.3 ± 7.6 kPa, respectively. All results of the water-wetted bubble point test were beyond the filter manufacturer’s minimum bubble point specification (344.8 kPa).

Conclusions

The bubble point test technique using the bubble point test kit was practical for routine quality control tests of PET radiopharmaceuticals.     

Radiosynthesis and ex vivo evaluation of (R)-(−)-2-chloro-N-[1-11C-propyl]n-propylnorapomorphine

IntroductionSeveral dopamine D₂ agonist radioligands have been used with positron emission tomography (PET), including [¹¹C-]-(?)-MNPA, [¹¹C-]-(?)-NPA and [¹¹C]-(+)-PHNO. These radioligands are considered particularly powerful for detection of endogenous dopamine release, but they either provide PET brain images with limited contrast or have affinity for both D₂ and D₃ receptors. We here present the carbon-11 radiolabeling and ex vivo evaluation of 2-Cl-(?)-NPA, a novel PET-tracer candidate with high in vitro D₂/D₃ selectivity.Methods2-Cl-[¹¹C]-(?)-NPA and [¹¹C]-(?)-NPA were synthesized by a two step N-acylation-reduction process using [¹¹C]-propionyl chloride. Awake rats were injected with either tracer, via the tail vein. The rats were decapitated at various times, the brains were removed and quickly dissected, and plasma metabolites were measured. Radioligand specificity, and P-glycoprotein involvement in brain uptake, was also assessed.Results2-Cl-[¹¹C]-(?)-NPA and [¹¹C]-(?)-NPA were produced in high specific activity and purity. 2-Cl-[¹¹C]-(?)-NPA accumulated slower in the striatum than [¹¹C]-(?)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[¹¹C]-(?)-NPA (standard uptake value 0.72±0.24) was approximately half that of [¹¹C]-(?)-NPA (standard uptake value 1.37±0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[¹¹C]-(?)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[¹¹C]-(?)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake.ConclusionEx vivo experiments showed, despite a favorable D₂/D₃ selectivity, that 2-Cl-[¹¹C]-(?)-NPA is inferior to [¹¹C]-(?)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.     

A measurement of the photon emission probabilities for the 161-, 303- and 384-keV γ-rays in the decay of 133Xe

The relative emission probabilities for the 161-, 303- and 384-keV γ-rays emitted during the decay of ¹³³Xe have been measured by comparing spectra obtained from a sample with spectra from standard ¹³³Ba sources. Corrections were made for random losses, differences in geometry, attenuation due to differing source encapsulation and coincident summing effects. From the corrected rates, the emission probabilities relative to the sum of the 80- and 81-keV γ-rays are 24.2±2.5 × 10⁻⁴, 1.93±0.07 × 10⁻⁴ and 0.90±0.04 × 10⁻⁴ for the 161-, 303- and 384-keV γ-rays respectively. If the sum of the 80- and 81-keV γ-ray emission probabilities is 0.383±0.007, the emission probabilities of the 161-, 303- and 384-keV γ-rays are 9.3±1.0 × 10⁻⁵ and 3.5±0.2 × 10⁻⁵ respectively. All uncertainties quoted here and in the following paper are one standard deviation equivalent unless otherwise stated.     

Postmortem sole incisions - a new sign of heroin overdose?

Postmortem sole incisions have been observed in a number of heroin overdose fatalities. Acqueintance of those victims confessed to producing those incisions as a life saving procedure in a futile attempt to help the comatose overdose victim. They thought that bleeding the unconscious victim would remove the overdose, in manner similar to bloodletting or phlebotomy which is still popular in the Gulf region. The presence of such wounds has become a first indication or rather "sign" of heroin poisoning. In such cases, laboratory investigation confirmed the pathologist's preliminary suspicion. In Dubai, postmortem sole incisions are important sign of death from heroin overdose even in the absence of other classical signs. This sign becomes more credible when accompanied by other signs and/or circumstantial evidence suggestive of heroin use. It is suggested that this should be called "bloodletting sign" of death from heroin overdose. The sign should not be confused with the self-inflicted cuts seen on the arms and forearms of drug misusers which are caused for other reasons.