REVIEW
`published: 11 September 2015
`doi: 10.3389/fmed.2015.00065
`
`Story of rubidium-82 and advantages
`for myocardial perfusion PET imaging
`
`Jean-François Chatal 1*, François Rouzet 2, Ferid Haddad 1, Cécile Bourdeau 1,
`Cédric Mathieu 3 and Dominique Le Guludec 2
`
`1 Groupement d’Intérêt Public Arronax, University of Nantes, Saint-Herblain, France, 2 UMR 1148, Department of Nuclear
`Medicine, Bichat Hospital, Assistance Publique Hôpitaux de Paris, DHU FIRE (Fibrosis, Inflammation, Remodeling in Cardio-
`vascular, Respiratory and Renal Diseases), Paris-Diderot University, Paris, France, 3 Department of Nuclear Medicine, Nantes
`University Hospital, Nantes, France
`
`Rubidium-82 has a long story, starting in 1954. After preclinical studies in dogs showing
`that myocardial uptake of this radionuclide was directly proportional to myocardial blood
`flow (MBF), clinical studies were performed in the 80s leading to an approval in the USA
`in 1989. From that time, thousands of patients have been tested and their results have
`been reported in three meta-analyses. Pooled patient-based sensitivity and specificity
`were, respectively, 0.91 and 0.90. By comparison with 99mTc-SPECT, 82Rb PET had a
`much better diagnostic accuracy, especially in obese patients with body mass index
`(cid:21)30 kg/m2 (85 versus 67% with SPECT) and in women with large breasts. A great
`advantage of 82Rb PET is its capacity to accurately quantify MBF. Quite importantly, it has
`been recently shown that coronary flow reserve is associated with adverse cardiovascular
`events independently of luminal angiographic severity. Moreover, coronary flow reserve
`is a functional parameter particularly useful in the estimate of microvascular dysfunction,
`such as in diabetes mellitus. Due to the very short half-life of rubidium-82, the effective
`dose calculated for a rest/stress test is roughly equivalent to the annual natural exposure
`and even less when stress-only is performed with a low activity compatible with a good
`image quality with the last generation 3D PET scanners. There is still some debate on the
`relative advantages of 82Rb PET with regard to 99mTc-SPECT. For the last 10 years, great
`technological advances substantially improved performances of SPECT with its accuracy
`getting closer to this of 82Rb/PET. Currently, the main advantages of PET are its capacity
`to accurately quantify MBF and to deliver a low radiation exposure.
`
`Keywords: rubidium-82, myocardial perfusion, PET imaging
`
`Introduction
`The story of medical use of rubidium goes back in 1954 when Love et al. showed that the biological
`behavior of rubidium was comparable to the one of potassium and that its myocardial muscle uptake
`was proportional to blood flow in coronary arteries (1). Following this paper, several preclinical
`studies have been performed mainly in dogs and using different radionuclides of rubidium until the
`early 80s when the first injection in humans took place (2). During the 80s, a few clinical studies,
`including hundreds of patients, demonstrated the good diagnostic accuracy of 82Rb/PET, which
`was higher than the one obtained with 99mTc/SPECT (3, 4). Subsequently, a generator 82Sr/82Rb
`(CardioGen-82®) was approved in 1989 and delivered in the USA by Bracco Diagnostics, Inc., for
`clinical use.
`
`Edited by:
`Denis Guilloteau,
`Université de Tours and CHRU Tours,
`France
`
`Reviewed by:
`Flavia Groppi,
`Università degli Studi di Milano, Italy
`Ulli Köster,
`Institut Laue-Langevin, France
`
`*Correspondence:
`Jean-François Chatal,
`GIP Arronax, 1, rue Aronnax,
`BP 10112, 44817 Saint-Herblain
`Cedex, France
`chatal@arronax-nantes.fr
`
`Specialty section:
`This article was submitted to Nuclear
`Medicine, a section of the journal
`Frontiers in Medicine
`
`Received: 16 June 2015
`Accepted: 26 August 2015
`Published: 11 September 2015
`
`Citation:
`Chatal J-F, Rouzet F, Haddad F,
`Bourdeau C, Mathieu C and
`Le Guludec D (2015) Story of
`rubidium-82 and advantages for
`myocardial perfusion PET imaging.
`Front. Med. 2:65.
`doi: 10.3389/fmed.2015.00065
`
`Frontiers in Medicine | www.frontiersin.org
`
`1
`
`September 2015 | Volume 2 | Article 65
`
`JUBILANT EXHIBIT 1025
`Jubilant v. Bracco, IPR2018-01449
`
`

`

`Chatal et al.
`
`Rubidium-82 for myocardial perfusion
`
`At that time, the number of PET cameras, their technological
`performances, and the production capacities of strontium-82 were
`limited, explaining a slow progression of this technology in the
`USA. However, despite this limitation, thousands of patients were
`tested with PET using rubidium-82 allowing three meta-analyses
`to be performed.
`During the last 10 years, with the increased number of PET/CT
`systems and the higher strontium-82 production capabilities, the
`number of patients injected with rubidium-82 in the USA dramat-
`ically grew even if it still represents a small percentage by com-
`parison with the use of 99mTc-sestamibi and 99mTc-tetrofosmin.
`Moreover, for the last 10 years, great technological advances have
`been introduced, including semiconductor detector SPECT scan-
`ners, novel collimator design, and novel iterative reconstruc-
`tion methods allowing to substantially improve count sensitivity
`and image resolution. Consequently, the diagnostic accuracy of
`99mTc/SPECT got closer to this of 82Rb/PET, opening a large debate
`on the advantages of one technique with regard to the other.
`The latest clinical developments zeroed in on the high prognos-
`tic value of quantification using PET and allowing to accurately
`measure myocardial blood flow (MBF) and coronary reserve.
`Even if there are no real technical limitations to such measure-
`ments with SPECT it will take some years before their poten-
`tial clinical validation (5). Finally, the level of radiation dose is
`an important parameter to be taken into consideration due to
`the high number of patients to be tested and the repetition of
`imaging in the same patients. The aforementioned technological
`advances allowed to significantly reduce radiation doses with both
`99mTc/SPECT and 82Rb/PET even if the latter delivers the smallest
`dose (6).
`
`Preclinical Studies
`Beta- and gamma-emitting rubidium-86 was first used because
`its long 18.7 days half-life enabled to perform long-lasting kinetic
`studies. In 1959, Love et al. showed, in 19 dogs, that myocardial
`uptake of this radionuclide was directly proportional to MBF (7).
`These results were confirmed 2 years later in 26 dogs by Levy
`et al. (8).
`More than a decade later, Nishiyama et al. compared opti-
`mal settings of scintillation camera with 201Tl (T1/2:73.1 h, γ:
`167 keV), 43K (T1/2: 22.2h, γ: 373 keV), 129Cs (T1/2: 32.06h,
`γ:372 keV), and 81Rb, a positron-emitting radioisotope with a half-
`life of 4.6 h (9). Thallium-201 was considered as the best suited
`with the available equipment at that time and cesium-129 was next
`best. High-energy photons from 81Rb largely made it impossible
`to obtain an interpretable image without the addition of more
`shielding.
`In 1979, Yano et al. compared several ion-exchange columns
`to be used in an automated 82Sr/82Rb generator for testing in
`man (10).
`Finally, in 1982, Selwyn et al. examined the relation between
`myocardial perfusion and rubidium-82 uptake during acute
`ischemia in six dogs after coronary stenosis and in five volun-
`teers and five patients with coronary artery disease. Myocardial
`tomograms, recorded at rest and after exercise in the volun-
`teers showed homogeneous uptake in reproducible and repeatable
`
`scans. An absolute mean decrease of 36 (cid:6) 14% in regional
`myocardial uptake was found after exercise in the patients with
`coronary artery disease (2).
`
`Clinical Studies
`
`Meta-Analyses of PET Studies
`Since the approval by FDA in the USA in 1989, a vast amount
`of clinical studies have been performed, including thousands of
`patients. Results have been analyzed in three meta-analyses pub-
`lished in 2008 and 2012 (Table 1). Pooled patient-based sensitivity
`and specificity were, respectively, 0.91 and 0.90. These excellent
`results should be tempered by some limitations and biases inher-
`ent to meta-analyses. There was heterogeneity between studies in
`scanning protocols and prevalence stenosis with invasive coro-
`narography. Moreover, baseline characteristics, such as gender
`or disease prevalence, were different between patient populations
`resulting in a cautious interpretation.
`For a long time, PET studies have been performed with
`two-dimensional cameras needing to inject a relatively high
`activity of rubidium-82 (40 mCi for stress-only) and resulting
`in non-negligible radiation exposure. The accuracy, outcomes,
`and cost-effectiveness of 3D PET technology using a low activ-
`ity of 20 mCi were recently evaluated in seven centers (14).
`Through an effective standardization and quality assurance pro-
`gram, the image interpretation was highly repeatable in involved
`centers.
`
`Meta-Analyses of SPECT Studies
`A much larger number of 227 studies using 99mTc/SPECT and
`including more than 14,500 patients have been considered in 7
`meta-analyses published between 1998 and 2012 (Table 2). Pooled
`patient-based sensitivity and specificity were, respectively, 0.88
`and 0.67. The same limitations as with PET studies were applied
`to SPECT studies.
`
`Comparison Between PET and SPECT
`Myocardial perfusion imaging is a real challenge in overweight
`or obese patients and in women with large breasts due to atten-
`uation artifacts, resulting in decreased specificity using 99mTc
`SPECT. PET imaging has improved specificity owing to better
`spatial resolution, coincidence detection, and accurate attenuation
`correction.
`Bateman et al. compared 99mTc SPECT in 112 patients with 82Rb
`PET in 112 patients (20). They showed a much better diagnostic
`accuracy using PET, in obese patients with body mass index (BMI)
`
`TABLE 1 | Results of meta-analyses with 82Rb PET.
`
`Number of
`studies/patients
`
`Patient-based
`sensitivity
`
`Patient-based
`specificity
`
`Reference
`
`0.93 (0.85–0.96)
`0.84 (0.81–0.87)
`0.91 (0.86–0.96)
`0.91
`
`0.90 (0.75–1.00)
`0.81 (0.74–0.87)
`0.93 (0.60–1.00)
`0.90
`
`(11)
`(12)
`(13)
`
`11/1175
`11/NSa
`6/843
`28/2018
`
`NS, not specified.
`aPooled results.
`
`Frontiers in Medicine | www.frontiersin.org
`
`2
`
`September 2015 | Volume 2 | Article 65
`
`

`

`Chatal et al.
`
`Rubidium-82 for myocardial perfusion
`
`TABLE 2 | Results of meta-analyses with 99mTc SPECT.
`
`Number of
`studies/patients
`
`Patient-based
`sensitivity
`
`Patient-based
`specificity
`
`Reference
`
`0.90 (0.89–0.90)
`0.87a
`0.89 (0.82–0.90)
`0.88a
`0.81a
`0.88 (0.88–0.89)
`0.85 (0.72–0.97)
`0.88 (0.81–0.90)
`
`0.77 (0.72–0.83)
`0.64a
`0.75 (0.65–0.75)
`0.67a
`0.65a
`0.61 (0.59–0.62)
`0.82 (0.76–0.92)
`0.67 (0.61–0.82)
`
`(15)
`(16)
`(17)
`(18)
`(19)
`(12)
`(13)
`
`20/3474
`27/3237
`44/2837
`10/651
`13/2922
`105/NS
`8/1410
`227/14531
`
`NS, not specified.
`aPooled results.
`
`(cid:21)30 kg/m2 (85 versus 67% with SPECT). However, it should be
`noted that SPECT was performed at that time without attenua-
`tion correction. With the introduction of iterative reconstruction,
`SPECT is now performed with attenuation correction, which may
`correct some artifacts and improve diagnostic accuracy in the
`obese population but with a decrease of sensitivity. A recent study
`reported on the value of 82Rb PET in 2687 obese patients with BMI
`(cid:21)30 kg/m2 by comparison with 2047 overweight patients (BMI:
`25.0–30.0 kg/m2) and 1303 normal patients (BMI: <25.0 kg/m2).
`Interestingly, the results showed the same prognostic value irre-
`spective of BMI (21).
`In the future, 82Rb PET should be compared to contempo-
`rary 99mTc SPECT using the last technological advances in the
`same overweight or obese patients to confirm or not the higher
`prognostic value of PET to SPECT.
`As aforementioned, a large number of clinical studies have
`been performed using PET and SPECT in different populations
`of patients allowing to group the results in meta-analyses with the
`possibility of biases in interpretation of these results.
`The most informative comparison between PET and SPECT
`should be in the same population of patients injected with both
`radiopharmaceuticals. Such comparisons have been made a long
`time ago at the time of approval of rubidium-82 in the USA
`in three studies, including a total of 433 patients (22–24). In
`fact, these studies used thallium-201 for SPECT, which has been
`replaced by technetium-99m. Quite recently, a comparison of
`both modalities has been performed in a small cohort of 27
`patients using the most recent hybrid imaging technology, which
`included CT-based attenuation correction for SPECT and PET
`(25). 82Rb/PET imaging was performed as a second-line test when
`previous gated rest/stress 99mTc/SPECT with or without atten-
`uation correction was non-conclusive. In this clinical situation,
`there were much fewer non-conclusive results with PET than with
`SPECT. Image quality and interpretive confidence were higher
`with PET than with SPECT even when SPECT was performed
`with attenuation correction.
`
`Dosimetric Studies
`Radiation dosimetry of rubidium-82 has been recently estimated
`in 10 healthy volunteers using the OLINDA/EXM 1.0 dosimetry
`software (26). Using different methodological approach, the esti-
`mates were discrepant with the results previously reported. The
`highest absorbed dose was delivered to the kidneys but remaining
`
`at a quite acceptable level of 1.3 cGy for 2220 MBq (60 mCi) of
`injected activity. The effective dose calculated for a rest/stress test
`with an injected activity of 2 MBq (cid:2) 1480 MBq (2 mCi (cid:2) 40 mCi)
`was 3.7 mSv that is roughly equivalent to the annual natural
`exposure.
`In 2015, Dorbala et al. reported on the way to reduce radiation
`dose with myocardial SPECT and PET imaging (6). Consider-
`ing the use of last generation of 3D PET scanners and software
`allowing to inject half activity of rubidium-82 (2 MBq (cid:2) 740 MBq
`or 2 mCi (cid:2) 20 mCi) for a preserved image quality, the calculated
`effective dose was 1.26 mSv for rest or stress. In the clinical situa-
`tion of stress-only 3D PET with MBF estimate, the radiation dose
`would be at an acceptable level of around 1 mSv. This is half of
`the radiation dose with 99mTc-sestamibi or tetrofosmin using last
`generation of scanners.
`
`Quantification Studies
`The clinical use of quantitative MBF assessment with 82Rb/PET
`started at the end of the previous decade in the USA. In 2009,
`El Fakhri et al. demonstrated, in 22 subjects including patients
`with known coronary artery disease or healthy volunteers, that the
`measurement of absolute quantitation of MBF was feasible, repro-
`ducible, and accurate (27). Two years later, Ziadi et al. prospec-
`tively evaluated the prognostic value of coronary flow reserve
`using 82Rb/PET in 704 patients and compared the results with
`semi-quantitative assessment using summed stress scores (28).
`They showed that quantitative myocardial flow reserve (MFR)
`was a good predictor of adverse cardiac events independent of the
`summed stress scores. The same added prognostic value of blood
`flow quantitation was confirmed 2 years later by Farhad et al. in
`351 patients (29).
`Several software packages are available for quantification of
`MBF. A study (RUBY-10) compared them in 48 patients from 10
`centers and showed that, using the most common kinetic model,
`they may be used interchangeably (30).
`The value of quantification of absolute MBF using rubidium-
`82 has been studied in 140 patients after heart transplant and for
`whom the prognosis depends on allograft vasculopathy (31). It
`was clearly shown that mean MFR was a significant predictor of
`future adverse events.
`The great interest of blood flow quantification has been doc-
`umented in diabetes mellitus (32). Among diabetic patients
`without coronary artery disease, those with impaired coronary
`reserve had cardiac event rates comparable to those with prior
`coronary artery disease, whereas those with preserved coronary
`reserve had cardiac event rates comparable to those of non-
`diabetics. Moreover, it has been recently shown that “global
`coronary flow reserve is associated with adverse cardiovascu-
`lar events independently of luminal angiographic severity and
`modifies the effect of early revascularization” (33). The angio-
`graphic severity was evaluated using the coronary artery disease
`prognostic index. This important result documents the com-
`plementary but distinct association of functional and anatomic
`coronary abnormalities. A significant interaction was shown
`between coronary flow reserve and revascularization strategy,
`which could have large implications in the future for therapeutic
`strategy.
`
`Frontiers in Medicine | www.frontiersin.org
`
`3
`
`September 2015 | Volume 2 | Article 65
`
`

`

`Chatal et al.
`
`Rubidium-82 for myocardial perfusion
`
`One other cardiac PET perfusion tracer, 13N-ammonia, has
`been approved in the USA and is being clinically used at a rela-
`tively modest level. Its positron range is favorable resulting in a
`good image resolution and the myocardial extraction fraction is
`also favorable but its short physical half-life of 9.96 min requires
`an onsite cyclotron, which is a great limitation for a routine clinical
`use. Another PET radiotracer, 18F-flurpiridaz is currently under-
`going a clinical phase III evaluation and is quite promising after
`its potential approval. It could then be a real competitor to 82Rb.
`A recent excellent review described in depth the characteristics of
`all PET perfusion radiotracers (34).
`
`Advantages
`
`Daily Availability of Rubidium-82 in Nuclear
`Cardiology Departments
`Like with all generators, rubidium-82 is daily available in a depart-
`ment of nuclear medicine after elution of the column loaded with
`strontium-82 (Table 3). Such elution can be repeated every 10 min
`making possible to inject up to 10–15 patients per day depending
`on the availability of a dedicated cardiac PET/CT and of patient
`recruitment rate. A 82Sr/82Rb generator can currently be used for
`28–42 days according to the loaded strontium-82 activity. It can be
`expected that this use will be extended to 60 days in a near future
`allowing to increase the number of tested patients with the same
`generator and consequently to decrease the cost of rubidium-82
`examination for each patient.
`
`Easy Interpretation of Images due to High Count
`Density
`The count density and the uniformity of distribution of rubidium-
`82 in the myocardium are higher with PET than with SPECT
`using technetium-99m, even using the last technological advances
`of both techniques (25). Consequently, the interpretative confi-
`dence and interreader agreement are higher with PET leading to a
`higher accuracy. PET cameras do not need the use of collimators,
`resulting in higher sensitivity and spatial resolution (35).
`
`Measurement of Myocardial Blood Flow and
`Coronary Reserve
`Interpretation of SPECT and PET images is visual or semi-
`quantitative and based on relative uptake. Myocardial areas with
`the highest uptake are supposed to be supplied by non-obstructive
`coronary arteries while those with decreased uptake during stress
`are considered as being supplied by obstructive arteries. A stenosis
`with a luminal diameter around 50% may be undetected by this
`visual interpretation. Moreover, patients with subclinical coro-
`nary ischemia or microvascular diffuse disease may present only
`
`TABLE 3 | Advantages and disadvantages of the use of 82Rb PET myocardial
`imaging.
`
`Advantages
`
`Disadvantages
`
`Quantification++
`Good interpretative confidence
`Favorable dosimetry
`Good diagnostic accuracy
`
`Cost++
`Lack of dedicated cardiac PET cameras
`Limited capacity of strontium production
`
`a mild heterogeneous or even homogeneous myocardial uptake.
`Finally, in the situation of three-vessel coronary disease, a reduc-
`tion of myocardial uptake may be balanced in all coronary arteries,
`resulting in a homogeneous left ventricle myocardium at stress
`(Figure 1).
`The measurements of absolute MBF in milliliter per gram per
`minute and MFR, which is the maximum increase in blood flow
`above the normal resting volume, allows to complete the field of
`application of conventional perfusion imaging by identifying sub-
`clinical coronary ischemia and characterizing extent and severity
`in multi-vessel disease. Moreover, it has been clearly shown during
`the last years that the measurement of hyperemic MBF and MFR
`using PET/CT may predict, better than other parameters, the
`occurrence of hard cardiac events.
`Today, there is no doubt that absolute myocardial perfusion
`quantification has been fully validated using PET/CT with 82Rb
`or 13N. There is a great debate about the same possibility using
`99mTc/SPECT. In a quite recent editorial, Garcia considered the
`current situation taking into account the most recent technolog-
`ical advances in instrumentation and quantification software (5).
`New heart-centered SPECT systems have a high count sensitivity
`and iterative reconstruction enables an efficient correction of
`attenuation, scatter, and resolution changes with depth. In 2013,
`Ben-Haim et al. (36) showed the feasibility of measuring MBF and
`MFR with SPECT. Today, it can be stated that there is no real
`limitation to the quantification of MBF and MBF reserve with
`SPECT. The first results on clinical efficacy using conventional
`SPECT/CT systems have been reported (37) but these preliminary
`results should be confirmed in large studies and it will take some
`years before full validation for clinical use. Today, there is no doubt
`that only PET technology allows to measure rapidly and accurately
`the MBF.
`
`Low Radiation Exposure for Patients
`Given the high and still increasing number of patients who have
`myocardial perfusion imaging all over the world each year, the
`radiation exposure for patients and medical staff is a real concern
`and should be reduced at the lowest level compatible with a good
`image quality.
`Effective radiation dose is directly related to the physical half-
`life of the radiopharmaceutical, its biodistribution and injected
`activity. In this respect, the very short half-life of 82Rb of 1.26 min
`in comparison of 6 h of 99mTc is quite favorable for a low radia-
`tion dose, especially if new technologies enable to substantially
`decrease injected activity. For a long time, using 2D imaging
`mode, injected activity of rubidium-82 for rest and stress was
`1480 MBq (40 mCi), resulting in an estimated dose of 2.5 and
`5 mSv, respectively (6). Shifting from 2D to 3D imaging mode
`allowed to inject half activity (740 MBq or 20 mCi) for the same
`image quality and then to reduce the dose to 1.3 mSv for stress
`or rest and even to <1 mSv using new estimates of rubidium-82
`dose (26). Such a dose is acceptable when compared to an average
`natural annual radiation dose of about 3 mSv. Stress-only PET
`3D imaging, allowing to measure hyperemic MBF with <1 mSv,
`would be the preferred strategy for risk stratification if this mea-
`surement is clinically validated with regard to the measurement
`of myocardial blood reserve, which needs both stress and rest
`tests.
`
`Frontiers in Medicine | www.frontiersin.org
`
`4
`
`September 2015 | Volume 2 | Article 65
`
`

`

`Chatal et al.
`
`Rubidium-82 for myocardial perfusion
`
`FIGURE 1 | A 56-year-old woman with a history of obesity (BMI: 31.2 cm/kg2), hypertension, hyperlipemia, and type 2 diabetes complicated of
`retinopathy and renal failure. The patient was referred to the Nuclear Medicine department for detection of coronary artery disease and underwent both
`Tc-99m-sestamibi SPECT (D-SPECT, Spectrum Dynamics, Haifa) and rubidium-82 PET/CT (Discovery 690 VCT, GEMS, Buc, France) as part of a clinical trial.
`SPECT (93% of the predicted maximal heart rate, no symptoms, EKG positive) was normal with a homogeneous uptake of the tracer both at stress and at rest (A).
`82Rb PET performed after Dipyridamole infusion showed a mild decrease of the tracer uptake in the lateral wall (arrow), completely reversible at rest, raising the
`suspicion of ischemia in the territory of the circumflex artery (B). This hypothesis was then confirmed by quantitative data derived from myocardial blood flow
`measurement with a coronary steal phenomenon in the same territory [coronary flow reserve (CFR) <1; (C)]. In addition, the CFR was markedly decreased (<1.5) in
`the territory of both the left descending artery and the right coronary artery, suggesting the presence of significant stenosis of these two coronary arteries. The
`coronary angiography confirmed the diagnosis of three-vessel disease and the patient underwent surgical revascularization. This case report underlines the greatest
`sensitivity of 82Rb PET over SPECT in the setting of balanced ischemia, in relation with the ability to perform absolute quantification of myocardial blood flow.
`
`By comparison, effective radiation doses are higher with 99mTc-
`based radiopharmaceuticals partially owing to the longer half-
`life of this radionuclide with regard to rubidium-82. Using the
`most recent advances in cardiac SPECT technology allowing to
`inject half activity for the same image quality [148–444 MBq
`(4–12 mCi)], the estimated doses are 2.3 and 8 mSv for rest/stress
`with 99mTc sestamibi and 2.0 and 6.1 mSv with 99mTc-tetrofosmin
`(6). Stress-only SPECT 3D imaging would deliver twice higher
`effective dose than with stress-only PET 3D imaging even if such
`dose remains moderate.
`A recent study reported on projected population cancer risks
`in the USA using myocardial perfusion scintigraphy (38). The
`authors considered estimated effective doses ranging from 9 mSv
`for stress-only technetium-99m to 35 mSv for a rest/stress dual-
`isotope study associating thallium-201 and technetium-99m and
`using conventional SPECT equipment. For rubidium-82 PET
`imaging, they considered an estimated effective dose of 15 mSv
`for a rest/stress test using an injected activity of 1480–2250 MBq
`and a 2D PET camera. Cancer risk projection models were based
`on the National Research Council Biological Effects of Ionizing
`Radiation VII report assuming a linear relationship with radiation
`exposure. In these conditions and considering the 9.1 million tests
`performed each year in the USA, the number of additional future
`cancers would be about 7400. This number should be viewed with
`great caution because, from the time of Berrington’s publication,
`estimated effective doses have been substantially decreased with
`the use of most advanced instrumentation allowing to dramati-
`cally decrease injected activities.
`
`Considering the lower injected activity, which is now possible
`with 3D SPECT and PET cameras, which results in low effective
`doses, the number of additional and supposed cancers should
`be significantly lowered. Finally, the risk/benefit ratio should be
`taken into consideration for each individual patient before per-
`forming a myocardial perfusion test and the lowest activity should
`be injected compatible with a good image quality leading to an
`accurate diagnosis.
`
`Limitations
`
`Cost
`Currently, the cost for one test with rubidium-82 is higher than
`with a 99mTc-labeled radiopharmaceutical even in the favorable
`situation of a nuclear cardiology center with a high recruitment
`rate (Table 3). In the USA, sestamibi-99mTc is currently reim-
`bursed at about $70 per dose, usually using 2 doses. However, in
`the hospital setting, the entire procedure including the drug is paid
`at $1139. Rubidium-82 is reimbursed at approximately $250 per
`dose. In the hospital setting, the entire procedure is reimbursed
`$1286.
`This relative low cost of technetium-99m is partly due to the fact
`that Mo-99/Tc-99m is not paid at full cost which explains some of
`the problems encountered nowadays with aging reactors and the
`difficulties to build new ones. Consequently, the use of rubidium-
`82 should be, at least at short term, limited to patients who are
`unable to complete exercise stress test, who are obese or who had
`a previous equivocal and non-conclusive SPECT test. Moreover,
`
`Frontiers in Medicine | www.frontiersin.org
`
`5
`
`September 2015 | Volume 2 | Article 65
`
`

`

`Chatal et al.
`
`Rubidium-82 for myocardial perfusion
`
`rubidium-82 should be used, despite its cost, when MBF and
`coronary flow reserve quantitation are required, for example, in
`patients with multi-vessel coronary disease.
`Some new high-energy cyclotrons will be installed shortly and
`will enable to extend strontium-82 availability, and then provide
`generators in a cost effective model.
`
`Limited Number and Availability of PET 3D
`Systems
`To be as cost-effective as possible with a 82Sr/82Rb generator, it
`is necessary to test a high number of patients before its expira-
`tion date (presently 28–42 days) but this situation needs to have
`available a dedicated cardiac PET/CT camera. In Europe, where
`a 82Sr/82Rb generator has not been approved yet, there is no
`such dedicated PET/CT cameras and the conventional PET/CT
`cameras are mainly used in oncology with fluorodeoxyglucose
`(FDG). A minimum of 8–10 patients are tested each day with
`this radiopharmaceutical and up to a maximum of 15–20 patients.
`Consequently, a quite limited number of patients could be injected
`with rubidium-82 per day making each test relatively expensive.
`This situation reinforces the fact that, at the beginning, Rb-82 will
`be probably limited to selective cases (see Cost). It will take prob-
`ably a few years before some dedicated cardiac PET/CT cameras
`are available in large cardiology centers with a recruitment rate
`warranting such equipment.
`
`Perspectives
`Strontium-82, which is the parent nucleus of rubidium-82, is
`produced using proton beam interacting on a target contain-
`ing stable rubidium. To be economically viable, an accelerator
`with proton beam of energy higher than 70 MeV and intensity
`>100 μA must be used. There are only few places in the world
`where such accelerators are available: Brookaven National Labora-
`tory (BNL-USA), Los Alamos National Laboratory (LANL-USA),
`iThemba labs (South Africa), INR (Russia), Triumf (Canada),
`and Arronax (France). These accelerators are not dedicated facil-
`ities and only part of the beam time is devoted to this produc-
`tion. Recently, based on the success of the first prototype of a
`70 MeV machine built by a commercial cyclotron provider and
`installed in Nantes (France), several private companies are con-
`sidering the use of such commercial cyclotron for strontium-82
`production. Zevacor (USA) is one of them and CDNM (Rus-
`sia) is the other one. In parallel, a 70 MeV cyclotron is being
`installed at Legnaro (Italy) for research purpose but one of the
`
`two available beam lines may be used for radionuclide produc-
`tion. This indicates that the availability of strontium-82 in the
`future will be higher allowing to secure the supply chain and
`enlarge the use of this radionuclide to other countries (at the
`moment only north America is using it routinely), especially in
`Europe.
`From a technological point of view, another advance will
`enlarge strontium-82 production, which is the use of rubidium
`metal target instead of the rubidium chloride target. With such
`change, higher yields can be obtained at the price of a more
`technical radiochemical process.
`Finally, several designs of strontium-82/rubidium-82 genera-
`tors are being studied and may reach the market in the future. This
`will allow to get generators with extended lifetime (up to 60 days)
`or lower activity which will better fit the need of users.
`
`Conclusion
`There is no doubt that the advantages of 82Rb/PET myocardial
`imaging have been clearly documented since its routine clinical
`use after approval in the USA nearly 30 years ago. For a long
`time, its accuracy was significantly better than that obtained with
`the SPECT/99mTc technology particularly in obese or overweight
`patients and women with large breasts due to attenuation correc-
`tion artifacts. With the most recent hybrid SPECT imaging tech-
`nology, the situation changed, leading to an improved specificity
`of 99mTc/SPECT. Currently, the main advantage of 82Rb/PET is its
`capacity to accurately measure the MBF and flow reserve. Even if
`such measurement is technologically feasible with 99mTc/SPECT,
`it will take some years before potential validation. Finally, given
`the very short physical half-life of rubidium-82, the radiation
`exposure rate with this radionuclide is significantly lower than
`with technetium-99m. Using 3D hybrid PET system, it is possible
`to inject low activities of rubidium-82 while maintaining a good
`image quality. The radiation exposure rate is then acceptable and
`inferior to natural exposure.
`in the future 82Rb/PET and
`It can be anticipated that
`99mTc/SPECT will continue to be used according availability of
`hybrid cameras and radionuclides.
`
`Acknowledgments
`This work has been supported in part by grants from the French
`National Agency for Research called “Investissements d’Avenir”
`Equipex ArronaxPlus no. ANR-11-EQPX-0004.
`
`References
`1. Love WD, Romney RB, Burch GE. A comparison of the distribution of potas-
`sium and exchangea