Munawwar Sajjad

Regional Myocardial Sympathetic Denervation Predicts the Risk of Sudden Cardiac Arrest in Ischemic Cardiomyopathy

OBJECTIVES The PAREPET (Prediction of ARrhythmic Events with Positron Emission Tomography) study sought to test the hypothesis that quantifying inhomogeneity in myocardial sympathetic innervation could identify patients at highest risk for sudden cardiac arrest (SCA). BACKGROUND Left ventricular ejection fraction (LVEF) is the only parameter identifying patients at risk of SCA who benefit from an implantable cardiac defibrillator (ICD). METHODS We prospectively enrolled 204 subjects with ischemic cardiomyopathy (LVEF ≤35%) eligible for primary prevention ICDs. Positron emission tomography (PET) was used to quantify myocardial sympathetic denervation ((11)C-meta-hydroxyephedrine [(11)C-HED]), perfusion ((13)N-ammonia) and viability (insulin-stimulated (18)F-2-deoxyglucose). The primary endpoint was SCA defined as arrhythmic death or ICD discharge for ventricular fibrillation or ventricular tachycardia >240 beats/min. RESULTS After 4.1 years follow-up, cause-specific SCA was 16.2%. Infarct volume (22 ± 7% vs. 19 ± 9% of left ventricle [LV]) and LVEF (24 ± 8% vs. 28 ± 9%) were not predictors of SCA. In contrast, patients developing SCA had greater amounts of sympathetic denervation (33 ± 10% vs. 26 ± 11% of LV; p = 0.001) reflecting viable, denervated myocardium. The lower tertiles of sympathetic denervation had SCA rates of 1.2%/year and 2.2%/year, whereas the highest tertile had a rate of 6.7%/year. Multivariate predictors of SCA were PET sympathetic denervation, left ventricular end-diastolic volume index, creatinine, and no angiotensin inhibition. With optimized cut-points, the absence of all 4 risk factors identified low risk (44% of cohort; SCA <1%/year); whereas ≥2 factors identified high risk (20% of cohort; SCA ∼12%/year). CONCLUSIONS In ischemic cardiomyopathy, sympathetic denervation assessed using (11)C-HED PET predicts cause-specific mortality from SCA independently of LVEF and infarct volume. This may provide an improved approach for the identification of patients most likely to benefit from an ICD. (Prediction of ARrhythmic Events With Positron Emission Tomography [PAREPET]; NCT01400334).

Production of iodine-124

Iodine-124 is produced in high yield by the124Te/d, 2n/124I reaction and >99.5% radionuclidic purity at 48 h post irradiation. The production yield was 0.55±0.06 mCi/μAh. Radiochemical separation and targetry methodology are described.

Synthesis of 15O-labeled butanol via organoborane chemistry.

Oxygen-15 labeled 1-butanol and 2-butanol were prepared by the reaction of O2-15O with tri-n-butylborane and tri-sec-butylborane in tetrahydrofuran. The reaction products were isolated and identified via reversed-phase high performance column chromatography and gas chromatography. Radiochemical yields of 50% (EOB) were obtained. The use of 15O-labeled butanol is suggested for cerebral blood flow measurements in conjunction with PET.

Excitation functions of (p, 2n) and (p, pn) reactions and differential and integral yields of 123I in proton induced nuclear reactions on highly enriched 124Xe

Excitation functions were measured for (p, 2n) and (p, pn) reactions on 99.9% enriched 124Xe from threshold up to 44 MeV. The (p, 2n) reaction is much stronger than the (p, pn) channel; above 36 MeV, however, the two processes have almost equal cross sections. Differential yields of 123I were measured experimentally as a function of proton energy and were also calculated from the excitation functions. Our experimental and theoretical yield data are consistent within 15%, but are lower by a factor of 2 than the literature experimental values. Our studies show that the optimum energy range for the production of 123I is Ep = 29 → 23 MeV. The theoretically expected thick target yield of 123I at 6.6 h after EOB is 11.2 mCi/μAh, and is in agreement with the high-current experimental production yields.

An automated [15O]H2O production and injection system for PET imaging

A computer controlled [15O]H2O injection system has been designed for multiple bolus injections during PET cerebral blood flow studies. The system is housed in a lead safe, and radiation exposure to nearby personnel is low; we have measured rates of approx. 100 microSv/h (10 mR/h) during 2 min of [15O]H2O production and < 50 microSv/h (< 5 mR/h) after 3.7 GBq (100 mCi) has been produced. Reproducibility studies show that the injected activity varies with a coefficient of variation of 2-3%.

Target preparation and recovery of enriched isotopes for medical radionuclide production

A remotely-driven internal target system with an improved stationary target head and manually controlled target transfer assembly was constructed. Methodology and techniques for the preparation of targets utilized for the routine production of 67Ga, 111In, 123I, 124I, and 201Tl with a CS-30 cyclotron are described. Experiences in recovery of isotopically enriched target materials are detailed for plating, radiochemical separation, and target recovery for 21 cycles with 68Zn; 18 cycles with 112Cd; 40 cycles with 124Te; and 24 cycles with 203Tl. This represented 84, 72, 145, and 196 targets for 67Ga, 111In, 123I + 124I, and 201Tl, respectively. Data on target stability under routine production conditions at high currents are summarized.

TSPO 18 kDa (PBR) Targeted Photosensitizers for Cancer Imaging (PET) and PDT.

Translocator protein (TSPO) 18 kDa overexpression has been observed in a large variety of human cancers, especially breast cancers. PK 11195, an isoquinoline analogue, is one of the ligands of highest TSPO binding affinity. Due to the long biological half life of our photosensitizers, there is a need to label them with a long lived radioisotope, for example I-124. Our objectives are to find translocator protein targeted photosensitizers for both tumor imaging (PET) and photodynamic therapy (PDT). I-PK 11195 is conjugated with the tumor avid photosensitizer HPPH. We find that those two tumor avid components complement each other and make the conjugate molecule even more tumor avid; compared to the photosensitizer itself, the conjugate is found to show improved PDT efficacy. It is concluded that I-PK 11195 can be a good vehicle to deliver radionuclide and photosensitizer to TSPO overexpressed tumor regions. Such conjugates could be useful for both tumor imaging (PET) and PDT.

Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder

It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen’s flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand 11C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.

Nuclear reaction cross sections relevant to the production of the 122Xe → 122I generator system using highly enriched 124Xe and a medium-sized cyclotron

Excitation functions were measured for the formation of 122mCs, 122Xe, 121Xe and 121I from threshold up to 44 MeV in proton induced nuclear reactions on 99.9% enriched 124Xe. The feasibility of 122Xe→122I generator production was investigated. The optimum energy range for the production of 122Xe is Ep = 43 → 35 MeV and the thick target yield amounts to 13.5 mCi/μAh. After an appropriate cooling time a generator containing several hundred mCi of 122Xe could be produced. The daughter 122I could be milked off periodically and would be >99% pure.

A semi-quantitative approach to the design, analysis and operation of a gas target system

Two-level factorial and central composite experimental designs were used to study the influence of operating conditions (pressure and beam current as an example) on gas target design for the production of medical radionuclides. Other aspects of design primarily the foil were analyzed to determine the effect of material properties or the expected performance of the target window. The use of empirical models relating the targets performance to operating conditions provides an adequate method to quantify properties of interest. These models can be readily incorporated into a computer-controlled system capable of updating their parameters, and performing further experiments while ensuring routine production requirements are met. The krypton gas target for the production of 81Rb was utilized as an example although the models are applicable to gas targets, in general.