New Myocardial Perfusion Imaging Agent [<sup> 99m </ Sup> Of Tc (n) (pnp5 The) (dbodc)] <sup> + </ Sup> Of Animal Studies

In order to circumvent the physical limitations (low-energy photons and long half-life)of ⁽²⁰¹⁾Tl, investigators have been attempted to develop suitable myocardial perfusion agentslabeled with technetium-99m (^(99m)Tc), a radioisotope with ideal physical properties forscintillation camera imaging. In the last two decades, great advances have been achieved,several kinds of ^(99m)Tc-labeled myocardial perfusion imaging agents have been developedand used clinically. Cationic ^(99m)Tc compounds, ^(99m)Tc-MIBI and ^(99m)Tc-tetrofosmin areroutinely used for clinical imaging with their favorable myocardial uptake and retentionproperties. Neutrally charged ^(99m)Tc complexes, ^(99m)Tc-teboromixe and ^(99m)TcN-NOET, exhibitbetter flow-extraction properties at high flows compared with these cationic agents and havecomplete redistribution similar to ⁽²⁰¹⁾Tl. Moreover, ^(99m)TcN-NOET is the first reportedcompound characterized by the presence of a terminal technetium-nitrogen multiple bond.Although the physical properties of ^(99m)Tc are better suited than ⁽²⁰¹⁾Tl forγ-cameraimaging, the organ biodistribution properties of these ^(99m)Tc-labeled tracers remainsuboptimal for myocardial perfusion imaging. Intense liver uptake and slow liver clearanceprolong the duration of imaging protocols. In particular, because of its close proximity to theheart, prolonged high liver uptake can make it difficult to accurately assess myocardialperfusion, particularly in the inferior or inferoapical left ventricular wall. Therefore, it isimportant to develop new tracers with improved organ biodistribution properties, with lessliver uptake.[^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ (technetium 99m [bis (dimethoxypropylphosphinoethyl)ethoxyethylamine]-[bis (N-ethoxyethyl) dithiocarbamato] nitride) is a new class nitrido^(99m)Tc agent that is currently under investigation. The core of this molecule consists of ^(99m)Tctriple bonded to nitrogen, and it is lipophilic, similar to ^(99m)TcN-NOET. However, unlike^(99m)TcN-NOET, which is a neutral molecule, [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ is monocationic,like ^(99m)Tc-MIBI and ^(99m)Tc-tetrofosmin.The goal of this experimental study was to determine the organ biodistribution andpharmacokinetics of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾, and to assess the characteristics of itsmyocardial imaging in canine models of acute myocardial ischemia. On the basis of thesestudies, we can evaluate preliminarily whether this compound can be used clinically as amyocardial perfusion imaging agent. PARTâ… Study of biodistribution properties of a new myocardial imaging agent [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾Objective: To study the biodistfibution properties of a new myocardial perfusion imagingagent [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ in rabbit models.Methods: Solution of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ for intravenous injection was prepared.The radiochemical purity was (95±0.52)%. Sixteen New Zealand rabbits were involved.Planar gamma imaging was performed at different times after the injection of imaging agent.The radioactivity changes of organs were calculated using regions of interest (ROI)technique. The 16 rabbits were divided into 4 groups and were executed at either 30, 60, 120,or 180 min after injection andγ-well counting was performed on excised organs.Results: Biodistribution in living rabbits showed, myocardial [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾uptake was high, but it was lower than ^(99m)Tc-MIBI during the whole imaging time.[^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ exhibited rapid lung clearance, similar to ^(99m)Tc-MIBI.Importantly, [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ cleared more rapidly from the liver than^(99m)Tc-MIBI. As early as 30min after injection, [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ heart-to-liverratio was nearly 1 (0.98±0.52) versus 0.56±0.19 for ^(99m)Tc-MIBI (p<0.01). By 60min,[^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ heart-to-liver ratio climbed to the peak (1.18±0.57) comparedwith 0.71±0.29 for ^(99m)Tc-MIBI (p<0.01). After 60min, the heart-to-liver ratio of[^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ kept in high level until 180min. The biodistribution in theisolated organs demonstrated the same trend.Conclusion: The rapid [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ liver clearance may shorten theduration of imaging protocols by allowing earlier image acquisition and may markedlyreduce the problem of photon scatter from the liver into the inferoapical wall on myocardialimages. So [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ is a promising new myocardial perfusion tracerwith superior biodistribution properties.PARTâ…¡Experimental study of a new myocardial perfusion imaging agent [^(99m)Tc(N)(PNPS)(DBODC)]⁽⁺⁾ in swineObjective: To determine the pharmacokinetics and organ biodistribution of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ in swine.Methods: Solution of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ for intravenous injection was prepared.The average labeling yield was (95.54±0.85)%. The pharmacokinetics, biodistribution andratio of T/NT were studied in 7 swine. The tracer was injected from the ear vein. Samples ofblood were collected from the femoral vein at 2, 5, 10, 15, 30, 45, 60, 75, 90, 120, 150 and180min, serial plane images were acquired meanwhile.Results: The pharmacokinetics of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ conformed totwo-compartment model, T_(1/2α)=(2.97±0.48)min, T_(1/2β)=(52.49±19.49)min, CL=(14314.29±8445.79)ml/h. The time-radioactivity curves showed that the liver uptake curves of[^(99m)Tc(N)(PNPS)(DBODC)]⁽⁺⁾ were below the myocardial curves after 30min post-injection,while that of ^(99m)Tc-MIBI were above the myocardial curves. The heart to liver activity ratioof the new agent was higher than ^(99m)Tc-MIBI during 30min～180min (p<0.05). The planarimages of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ from 5 to 180min showed good quality with lowerlung and liver radioactivities. The rapid liver clearance of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ notonly may reduce photon scatter from the liver into the inferior walls on myocardial perfusionimaging, but also may shorten the duration of imaging protocols.Conclusion: The results of this study show that the [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ is veryworth further investigation as a potential myocardial perfusion imaging agent.PARTâ…¢Myocardial perfusion imaging with [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ in canine model of acute myocardial ischemiaObjective: To assess the characteristics of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ myocardial imagingin canine models of acute myocardial ischemia, and compared with ^(99m)Tc-MIBI.Methods: Twelve adult beagle dogs were included in this study. The left anterior descendingartery (LAD) was occluded to make a critical stenosis (>90%), then, adenosine was infusedintravenously at a rate of 0.14mg/kg-min for 6min. At the end of 3min of adenosine infusion,185MBq of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ or ^(99m)Tc-MIBI (randomly) was injectedintravenously. The occluder was released after adenosine infusion. Serial myocardial SPECT imaging acquisitions were obtained 0.5, 1, 1.5 and 2hr after tracer injection, respectively.Rest myocardial SPECT imaging was acquired in the next day.Results: [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ exhibited high heart uptake and minimal lung uptake,that was similar with ^(99m)Tc-MIBI. No significant myocardial washout was observed withboth tracers over a period of 2 hours. [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ clearance from the liverwas obviously more rapid than that with ^(99m)Tc-MIBI (heart-liver radio at 60min, 1.36±0.43versus 0.58±0.21, p=0.005). [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ could detect myocardial ischemia,and the ability of it to detect myocardial ischemia was comparable to ^(99m)Tc-MIBI([^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ detected 3.60±1.52 defect segments, ^(99m)Tc-MIBI detected4.25±0.96 defect segments, p=0.48). Like ^(99m)Tc-MIBI, [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ showedminimal redistribution. The image quality of [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ was better than^(99m)Tc-MIBI.Conclusion: With the exception of the more rapid liver clearance, many of the properties of[^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ that were observed in this canine study were comparable tothose of ^(99m)Tc-MIBI. So [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ is a very promising new myocardialperfusion imaging agent for further clinical study.Final conclusion: These studies indicated favorable heart uptake and retention of[^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ in different animal species. Its lung uptake was low.Importantly, [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ clearance from the liver was obviously more rapidthan that with ^(99m)Tc-MIBI. At rest and after pharmaceutical stress, favorable ratio of T/NTcould be acquired as early as 30min postinjection. The biodistribution properties of[^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ were superior to ^(99m)Tc-MIBI, and its ability to detectmyocardial ischemia was comparable to ^(99m)Tc-MIBI. Combining all of the favorableproperties of ^(99m)Tc-MIBI with more rapid liver clearance makes [^(99m)Tc(N)(PNP5)(DBODC)]⁽⁺⁾ a very promising new agent for clinical myocardial perfusion imaging.