Cardiac Pipeline: What Radiopharmaceuticals Offer

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Source: JNM-cardiac-2.jpg - JNM-cardiac
Targeted imaging of atherosclerosis. (A) 18F-4V PET/CT of VCAM-1 expression. (B) Higher uptake is seen in ApoE 2/2 mice than in statin-treated mice. (C) Nanoparticle PET/CT of macrophages. (D) MRI with pseudocolored T2-weighted signal intensity, which decreased because of accumulation of iron oxide nanoparticles.

Multiple radiopharmaceuticals in the development pipeline are showing promise in cardiology. One expert shared some of the radiopharmaceuticals that inspire the most enthusiasm.

An investigational tracer called F-18 flurpiridaz shows a great deal of promise in cardiac imaging, according to Marcelo F. Di Carli, MD, professor of radiology at Harvard Medical School in Boston. F-18 flurpiridaz is currently under development for the evaluation of PET myocardial perfusion and it has some winning qualities, one of which is very high extraction by the myocardium. This allows clinicians to clearly delineate with high sensitivity areas of diseased coronary arteries and more so than other tracers.

“The image quality that has been reported in Phase 2 clinical trials is very impressive as compared to SPECT imaging,” explains Di Carli. “The other issue is that if approved, after Phase 3 clinical trials, this tracer can be distributed on a unit-dose basis so you don’t need to purchase an expensive generator, for example, as with Rubidium-82 or a cyclotron for N-13 ammonia. This tracer would make cardiac PET imaging much more available to a wider range of patients.”

Perfusion is not the only route for detecting cardiac disease. Imaging sympathetic innervation of the heart has been gaining some attention, with one major tracer leading the way: Iodine-123 metaiodobenzylguanidine (I-123 MIBG). A large-scale clinical trial for patients with heart failure demonstrated the tracer’s efficacy in improving patient risk stratification, helping clinicians to predict who has a lower risk of sudden cardiac death and to select patients for defibrillators (J Am Coll Cardiol 2010:55[20]:2212–2221).

“This tracer has been approved by the FDA as of April and we will likely see more use of this tracer, which is imaged with SPECT,” says Di Carli, who mentioned that PET-emitter counterparts similar to MIBG agents are being developed but have a long way to go before they could be approved. Once that happens, these PET alternatives would offer significantly improved image quality and quantitation and not only regional but global sympathetic nerve dysfunction.

Imaging of atherosclerotic plaques is another application where agents are emerging. Tracers that target translocator protein (TSPO), the membrane intracellular protein that is over-expressed in inflammatory cells within atherosclerotic plaques, could potentially tell clinicians about a patient’s level of coronary disease.

“These tracers have been shown in various forms both in preclinical and clinical studies that they may be a better alternative for detecting so-called vulnerable plaques compared to FDG, for example,” says Di Carli. “There have been a few publications about these TSPO agents using carbon-11. The compound that was used was PK-11195. In that publication, the investigators showed that it may offer an improved target to background contrast in terms of detecting atherosclerotic plaques and newer agents are being developed with fluorine-18, which has a much longer half-life and improved imaging characteristics. Those are potentially promising for looking at vascular inflammation.”

However, Di Carli notes TSPO agents would not have the same value for imaging of the myocardium, as background production of TSPO occurs in normal heart muscle. Something along these lines for vascular imaging could reach FDA approval within three to five years, he estimates.

 

 - GatedTransversePETGated transverse PET images in vivo. End-diastolic transverse PET images at last time in for sham mice, TAC mice, and TAC mice treated with propranolol at baseline, day 1, and day 7 after surgery are shown. All scans are from same animals. Images indicate enlargement in left ventricular (LV) cavity in TAC mice over 7 d. Images also show increase in 18 F-FDG uptake in TAC mice starting at day 1, indicative of metabolic adaptation in pressure-overload LV hypertrophy. Source: J Nucl Med 2013; 54:1-7

Capturing cardiac remodeling

PET evidence of cardiac remodeling is accumulating in the literature, which stands to bolster the use of a range of predictive biomarkers.

“The most robust papers have used MMP-targeted (matrix metalloproteinase) tracers to evaluate healing after myocardial infarction and predict adverse cardiac remodeling after infarction. Other tracers that have been used for this purpose but that have less validation include tracers assessing angiotensin-converting enzyme activity and tracers targeting inflammation (e.g. FDG) after myocardial infarction,” says Di Carli.

It has not been determined whether these methods will have a significant impact on patient management. Further research will have to be conducted to see if these techniques could be used for patient selection for preventative therapies targeting cardiac remodeling. “[It’s] a very tall order for any of these tracers. Alternatively, these approaches may be useful in drug development and possibly clinical trials.”

At the vanguard of cardiac molecular imaging is the use of nanoparticles for increasingly targeted and finely engineered imaging agents. An example of this is the use of dextran nanoparticles to capture monocyte and macrophage activity in atherosclerotic plaques using both hybrid PET/MR and near infrared imaging (Circulation Res 2013; 112[5]: 755–761).

“Oftentimes we can’t tell the underlying cause and diagnostic certainty is important,” says Di Carli. “This is an area of clearly unmet need in imaging in general, but it is an area that is quite amenable to molecular imaging.”

Eye on quantification

Cardiac PET studies have shown that myocardial blood flow and coronary flow reserve can fine-tune risk stratification further than conventional cardiac imaging (Circulation 2011;124:2215-2224).

Currently Ru-82 and N-13 ammonia are approved in the U.S. and have been validated for quantifying both of these cardiac measures; instrumentation as well as quantitative software is now more widely available. “We are seeing a lot more use of quantitative coronary flow reserve than we were seeing five years ago,” explains Di Carli. “You need tracers that are highly extractable by the heart muscle in order to do that. The only technique that can do it is PET imaging, for various technical reasons.”

Once approved, F-18 flurpiridaz represents an even more powerful agent for improving the accuracy of these quantitative operations, he continues.
A challenge for all of these and other tracers is that the bar for gaining regulatory approval has been raised, particularly for coronary disease, and it is no easy feat to prove that new tracers will define disease better than existing tracers. This is especially the case for those agents that cost significantly more than conventional methods.

“That is the clear issue with PET imaging,” says Di Carli. “It is unlikely that there will be another tracer approved without demonstrating superiority compared to existing techniques.”