18F-mFBG Imaging for Myocardial Sympathetic Innervation

The focus of most research into myocardial sympathetic neuronal imaging has been on NE analogues labeled with gamma- or positron-emitting radioisotopes. The most widely studied conventional nuclear imaging agent is 123I-metaiodobenzylguanidine (123I-mIBG), which provides effective and well-validated semi-quantitative information. In the pivotal trial (ADMIRE-HF) on which the US approval of 123I-mIBG for cardiac imaging was based, there was an increased occurrence of adverse outcomes (composite of HF progression, potentially fatal arrhythmias, and cardiac death) in HF subjects based upon the heart/mediastinum (H/M) ratio on late ("delayed") planar 123I-mIBG (AdreView™) images. Analyses of all-cause mortality in the ADMIRE-HFX extension study confirmed the low risk associated with H/M ≥1.60 (2-year mortality of 4%). Subsequent analyses specifically focused on arrhythmic events suggested that sympathetic neuronal imaging could aid in discriminating between low and higher risk cohorts. However, 123I-mIBG imaging results are heavily dependent on the imaging equipment and acquisition techniques used, and global standardization efforts have had limited success. In addition, absolute quantitation of myocardial uptake and clearance kinetics cannot be effectively achieved using single-photon emission computed tomography (SPECT), even with use of attenuation and scatter correction methods. These limitations and the high cost of the procedure have severely limited its use in clinical practice. The preferred nuclear technique for high-resolution quantitative imaging of cellular functional behavior is PET. The present research will utilize a new 18F-labeled radiopharmaceutical, 18F-meta-fluorobenzylguanidine (18F-mFBG). The greatest advantage of this agent is its structural equivalence to 123I-mIBG, with the 123I atom in the latter replaced by a 18F atom. The vast clinical and research experience with mIBG provides a strong basis for the expected performance of 18F-mFBG. In addition, animal and limited human experience suggests that clearance of 18F-mFBG from blood and certain target organs is more rapid than mIBG, such that target-background ratios (TBRs) for the heart should be superior for 18F-mFBG, improving both image quality and reliability of global and regional myocardial quantitation. To date, the focus of most research using 18F-mFBG has been on its use as an imaging agent for neural crest tumors such as neuroblastoma and pheochromocytoma (22). However, analyses of myocardial 18F-mFBG uptake in patients being evaluated for neural crest tumors suggested this agent could be effective as a cardiac imaging agent. Past analyses of cardiac sympathetic imaging results have suggested this method might be of value for identifying heart disease patients at greater risk for arrhythmic events and sudden cardiac arrest (SCA). The largest prospective study on this topic enrolled 204 subjects eligible for implantable cardioverter defibrillators (LVEF ≤35%) who underwent cardiac PET imaging for myocardial sympathetic denervation using 11C-meta-hydroxyephedrine (11C-HED). The results showed that volume of denervated myocardium had the strongest correlation with SCA (arrhythmic death or defibrillator discharge). The 33 subjects with SCA had significantly larger denervated volumes than the 171 subjects without SCA (33±10% vs 26±11%; p\<0.001). Multivariate analysis revealed that presence of 2 or more of risk factors of sympathetic denervation \>37.6% of LV, LV end-diastolic index \>99 ml/M2, creatinine \>1.49 mg/dl, and no anti-angiotensin medication predicted a nearly 50% event rate over 4 years vs \<1% annual rate without these risk factors (p \< 0.0001). The rationale for the present study is twofold. 1. Correlate areas of cardiac denervation with accurate measurements of regional cardiac blood flow (CBF) and inducible ischemia using standardized 82Rb PET. 2. Determine variables of sympathetic innervation and CBF most strongly related to past occurrence of arrhythmic events. With the greater sensitivity and resolution of PET imaging compared to planar and SPECT techniques, it is expected that 18F -mFBG imaging will detect abnormalities that are missed with 123I mIBG and provide the reliable and reproducible quantitative accuracy necessary to support use of this agent for clinical patient studies.