Hypoxia-Imaging Agent [123I]IAZA in Healthy Adults

The objective of this work is to evaluate the potential effect of cardiac stress exercise on 16 the accumulation of [123I]IAZA, a radiopharmaceutical used to image focal tissue hypoxia, in 17 otherwise normal myocardium in healthy volunteers, and to determine the impact of exercise on 18 [123I]IAZA pharmacokinetics. The underlying goal is to establish a rational basis and a baseline for 19 studies of focal myocardial hypoxia in cardiac patients using [123I]IAZA. Three healthy male 20 volunteers ran the ‘Bruce’ treadmill protocol, a clinically-accepted protocol designed to expose 21 myocardial ischemia in patients. The ‘Bruce’ criterion heart rate is 85% of [220 – age]. 22 Approximately one minute before reaching this level, [123I]IAZA (5.0 mCi/0.85 mg) was 23 administered as a slow (1–3 min) single intravenous (i.v.) injection via an indwelling venous 24 catheter. The volunteer continued running for an additional 1 min before being transferred to a 25 gamma camera. Serum samples were collected from the arm contralateral to the administration site 26 at pre-determined intervals from 1 min to 45 h post injection and were analyzed by radio HPLC. 27 Pharmacokinetic (PK) parameters were derived for [123I]IAZA and total radioactivity (total[123I]) 28 using compartmental and noncompartmental analyses. Whole-body planar scintigraphic images 29 were acquired from 0.75 to 24 h after dosing. PK data and scintigraphic images were compared to 30 previously published [123I]IAZA data from healthy volunteers rest. Following exercise stress, both 31 [123I]IAZA and total[123I] exhibited bi-exponential decline profiles, with rapid distribution phases 32 [half-lives (t1/2α) of 1.2 and 1.4 min, respectively], followed by slower elimination phases [t1/2β of 195 33 and 290 min, respectively]. Total body clearance (CLTB) and the steady state volume of 34 distribution (Vss) were 0.647 L/kg and 185 mL/min, respectively, for [123I]IAZA and 0.785 L/kg and 35 135 mL/min, respectively, for total[123I]. The t1/2β, CLTB and Vss values were comparable to those 36 reported previously for rested volunteers. The t1/2α was approximately 4-fold shorter for [123I]IAZA 37 and approximately 3-fold shorter for total[123I] under exercise relative to rested subjects. The heart 38 region was visualized in early whole body scintigraphic images, but later images showed no 39 accumulated radioactivity in this region, and no differences from images reported for rested 40 volunteers were apparent. Minimal uptake of radiotracer in myocardium and skeletal muscle was 41 consistent with uptake in non-stressed myocardium. Whole-body scintigrams for [123I]IAZA in 42 exercise-stressed healthy volunteers were indistinguishable from images of non-exercised 43 volunteers. There was no evidence of hypoxia-dependent binding in exercised but otherwise 44 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 February 2018 doi:10.20944/preprints201710.0034.v2 © 2018 by the author(s). Distributed under a Creative Commons CC BY license. healthy myocardium, supporting the conclusion that exercise stress at Bruce protocol intensity 45 does not induce measurable myocardial hypoxia. Effects of exercise on PK parameters were 46 minimal; specifically, the t1/2α was shortened, reflecting increased cardiac output associated with 47 exercise. It is concluded that because [123I]IAZA was not metabolically bound in exercise-stressed 48 myocardium, a stress test will not create elevated myocardial background that would mask regions 49 of myocardial perfusion deficiency. [123I]IAZA would therefore be suitable for the detection of 50 viable, hypoxic myocardium in patients undergoing stress-test-based diagnosis. 51