Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Med Chem. Author manuscript; available in PMC 2012 September 1.
Published in final edited form as:
PMCID: PMC3184346

86Y based PET radiopharmaceuticals: radiochemistry and biological applications


Development of targeted radionuclide therapy with 90Y labeled antibodies and peptides has gained momentum in the past decade due to the successes of 90Y-ibritumomab tiuxetan and 90Y-DOTA-Phe1-Tyr3-octreotide in treatment of cancer. 90Y is a pure β-emitter and cannot be imaged for patient-specific dosimetry which is essential for pre-therapeutic treatment planning and accurate absorbed dose estimation in individual patients to mitigate radiation related risks. This review article describes the utility of 86Y, a positron emitter (33%) with a 14.7-h half-life that can be imaged by positron emission tomography and used as an isotopically matched surrogate radionuclide for 90Y radiation doses estimations. This review discusses various aspects involved in the development of 86Y labeled radiopharmaceuticals with the specific emphasis on the radiochemistry and biological applications with antibodies and peptides.

Keywords: PET imaging, radiochemistry, 90Y, 86Y, bioconjugate chemistry, peptides, and antibodies


Recent advances in radiochemistry and biomedical sciences offer diverse receptor-avid and immune-derived molecular vectors as well as a plethora of therapeutic radionuclides [1,2]. Several systems are currently being investigated as potential means for targeting of radionuclide to desired site. Of these, largely monoclonal antibodies (mAb) and peptides have successfully been used in clinic [1,2]. Targeted radionuclide therapy with antibodies and peptides are at the forefront of molecular cancer treatment modalities. 90Y is one of the promising radionuclides for targeted radionuclide therapy of hematologic malignancies and solid tumors [36]. However, 90Y labeled antibodies and peptides may pose challenges in managing radiation toxicity if the radiation doses exceed the critical limit to organs such as the bone marrow and the kidneys [7,8]. Since 90Y is a pure β-emitter, its biodistribution cannot be readily imaged for patient-specific dosimetry which is essential for pre-therapeutic treatment planning and accurate absorbed dose estimation in individual patients to mitigate radiation risks. Attempts have been made to image the Bremsstrahlung radiation generated by the slowing down of high-energy electrons in tissue. However, the low photon yield and the polychromatic nature of the Bremsstrahlung spectrum result in limited quantitative accuracy with 90Y [9,10].

111In and 89Zr were used as surrogate single photon emission computerized tomography (SPECT) and positron emission tomography (PET) radionuclides for 90Y, respectively; however, disparities were observed in the biodistribution of these radionuclides and the 90Y labeled antibodies and peptides [1115]. The somatostatin receptor-targeted 90Y-DOTA-Phe1-Tyr3-octreotide is the most extensively studied radiolabeled peptide in patients for treatment of cancer. Clinical trials performed in several countries showed complete and partial remissions in 10% to 30% of patients [1]. In spite of encouraging efficacy results, loss of renal function or renal failure was observed in some patients treated with 90Y-DOTA-Phe1-Tyr3-octreotide and therefore pre-treatment radiation dose assessments are critical for 90Y-DOTA-Phe1-Tyr3-octreotide [1,8]. In a clinical study, a 86Y labeled peptide and 111In labeled peptide were compared for pre-treatment dosimetry assessments of 90Y radionuclide therapy [11] Compared to 86Y-DOTA-Phe1-Tyr3-octreotide, dosimetry with 111In-pentetreotide overestimated doses to kidneys and spleen, whereas the radiation dose to the tumor-free liver was then underestimated for 90Y-DOTA-Phe1-Tyr3-octreotide radiotherapy [11].

In recent years, 86Y has gained popularity as an attractive surrogate for studying 90Y due its half-life (14. 7 h) and positron emission (33 % β+) which allows quantitative imaging over 2–3 days [11,16]. Since the chemical form is identical to 90Y, 86Y labeled antibodies and peptides have identical biodistributions with 90Y labeled antibodies and peptides, and therefore should inherently enable more accurate absorbed dose estimates for 90Y [11,17,18]. This review discusses various aspects involved in the development of 86Y labeled radiopharmaceuticals with the specific emphasis on the radiochemistry and biological applications with antibodies and peptides.


Yttrium belongs to group IIIB of the periodic table and has an atomic radius of 2.3 Å and electronegativity of 1.22. 86Y can be produced via the (p,n) or (d,2n) nuclear reaction on enriched 86Sr (3He,2n) on natural rubidium, (p,3n) on enriched 88Sr, or (d,x) reaction on natural zirconium target [19,20]. However, the 86Sr(p,n)86Y reaction is the more commonly used method as it can be applied on medical cyclotrons by irradiating SrCO3 or SrO with 2–6 μA of beam current for <4 h [21,22]. As compared to SrCO3, SrO is a superior target because it can withstand at least a 6 μA of beam current, which is a significant improvement over a maximum of 2 μA on the SrCO3 target, resulting in yields that are almost double with minimum contaminants [21]. After irradiation, 86Y is separated from the target material using a commercially available Sr(II) selective resin and purified in order to accomplish efficient radiolabeling [22]. Electrochemical method of separation is also commonly used to produce no-carrier-added 86Y of high purity [23]. Other separation techniques include the combination of co-precipitation and cation-exchange chromatography and ion specific resin chromatography, or paper filtration from alkaline solution [18,19,24].

Once high purity 86Y is produced, it is then attached to the targeting vector such as an antibody and a peptide via a chelating agent. A chelating agent is a molecule containing more than one ligand or an atom such as N, O and S that can donate a lone pair of electrons. The oxidation state and electronegativity play a major role in the formation of metal-ligand complexes. Yttrium is a transition metal ion that exists in a tricationic state, Y(III), that can readily reach coordination numbers of 8 and 9 in its complexes and prefers octadentate coordinating ligands. Acyclic polyaminocarboxylates such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriamine pentaacetic acid (DTPA) and macrocyclic polyaminocarboxylates such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) have been used as chelating agents for yttrium (Figure 1).

Figure 1
Chemical structures of acyclic and macrocylic polyaminocarboxylates chelating agents used for radiolabeling with yttrium

The chelating agents themselves are modified to provide a method to link them to antibodies and peptides (e.g., cyclic and mixed anhydrides of DTPA), alternatively linking groups such as isothiocyanatobenzyl group (SCN-Bz) are incorporated to the chelating agent by covalent linkage to the carbon backbone of the chelating agents [25]. In a pre-clinical study, the biodistribution of yttrium- and indium-labeled mAb B72.3 was compared in athymic mice bearing human colorectal cancer LS-174T tumors using three different chelate conjugates (SCN-Bz-EDTA, Cyclic anhydride-DTPA (ca-DTPA), and SCN-Bz-DTPA) [26]. The yttrium uptake in the bone with the SCN-Bz-EDTA and ca-DTPA conjugated mAb was greater then 14 and 11% ID/g, respectively, while 88Y-SCN-Bz-DTPA-B72.3 showed only 3% ID/g. In contrast, the 111In-labeled B72.3 uptake in the bone with all three chelate conjugates was 2–3% ID/g. The differences in yttrium- versus indium-labeled mAb biodistributions demonstrates the differences in the in vivo stability of different forms of acyclic polyaminocarboxylates for In(III) and Y(III); all three chelating agents were stable for 111In, but only the full DTPA with 3 amines and 5 carboxylate donors bound to the Y(III) was stable for 88Y, thereby elucidating the need for both better and more stable chelating agents for Y(III) and the need for a radioistopically matched imageable yttrium radionuclide to predict more accurate biodistribution and dosimetry of 90Y-labeled agent [26].

To further understand and improve the in vivo stability, additional studies were performed with backbone-substituted forms of the SCN-Bz-DTPA and DOTA [27]. In this study, the biodistribution of yttrium-and indium-labeled mAb, B3, using two different chelate conjugates, i.e. 2-(p-SCN-Bz)-6-methyl-DTPA (1B4M-DTPA) and 2-(p-SCN-Bz)-1,4,7,10 tetraazacyclododecane tetraacetic acid (C-DOTA) (Figure 1) were compared in tumor bearing athymic mice [27]. Mice injected with indium and yttrium labeled 1B4M-DTPA-B3 showed a similar biodistribution in all tissues except the bones, where significantly higher accretion of yttrium than indium was observed, with 2.8% +/− 0.2% vs. 1.3% +/− 0.16% ID/g in the femur at 168 h, respectively (P < 0.0001) [27]. In contrast, mice receiving indium and yttrium labeled C-DOTA-B3 showed significantly higher accumulation of indium than yttrium in most tissues, including the bones and therefore further illustrating the differences between two radionuclides and the chelating agents. From these studies, it was observed that the SCN-Bz substituted onto the carbon backbone of DTPA for use in linkage to the antibody and the methyl groups incorporated onto the backbone sterically hindered the release of yttrium from the chelate and therefore demonstrated the superiority of backbone-substituted DTPA chelating agents over cyclic anhydride-DTPA chelating agents.

With a better understanding of the coordination chemistry and geometry of DTPA derivatives, a cyclohexyl derivative of DTPA (CHX-DTPA) was developed, which demonstrated excellent stability in vitro and in vivo [25,28,29]. Interestingly, the stereochemistry of CHX-DTPA played a major role in the in vivo stability of yttrium labeled agents and subsequent bone uptake. The single enantiomeric [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA) radioimmunoconjugate was found to be more stable as compared to the corresponding diastereomeric pair of CHX-B-DTPA radioimmunoconjugates (Figure 1). After 7 days post-injection, bone uptake of the yttrium labeled CHX-B′-DTPA or CHX-B″-DTPA radioimmunoconjugates was 5 times higher than that of the yttrium labeled CHX-A″-DTPA radioimmunoconjugate [28,30]. For labeling of peptides at the N-terminus, an N-hydroxysuccinimidyl penta-tert-butyl ester derivative of CHX-A″–DTPA featuring a glutaric acid spacer was developed (Figure 2) [31] In order to further improve the stability, DOTA derivatives such as SCN-Bz-DOTA were explored for radiolabeling antibodies and peptides with yttrium [3234]. In a comparative study, it was found that DOTA conjugated antibody was more stable than the DTPA conjugated [33]. Since then, numerous pre-clinical and clinical studies have been published reporting DTPA and DOTA based chelating agents for 90Y radionuclide therapy and thus extrapolating to 86Y for PET imaging [15,16,31,35].

Figure 2
Succinimidyl ester coupling chemistry for N-terminal conjugation of octreotide with N-hydroxysuccinimidyl penta-tert-butyl ester derivative of CHX-A″-DTPA with a glutaric acid spacer.

For in vivo applications, kinetic inertness of yttrium–chelator complexes or conjugates is more relevant than thermodynamic stability [36]. For yttrium, acyclic chelating agents are less kinetically inert than macrocyclic complexes of comparable stability, but at the same time acyclic chelating agents have faster metal-binding kinetics at room temperature compared with their macrocyclic analogues, which can be a significant advantage for radiolabeling of antibodies which are thermosensitive.

Biological applications

86Y labeled peptides

86Y labeled somatostatin receptor-targeted peptides were evaluated in rodents, non-human primates and humans [11,18,31]. For peptides, CHX-A″-DTPA, a widely applicable chelating agent for yttrium was modified via standard succinimidyl ester coupling chemistry for N-terminal conjugation to somatostatin peptide [31]. Briefly, an N-hydroxysuccinimidyl penta-tert-butyl ester derivative of CHX-A″-DTPA with a glutaric acid spacer moiety was developed to lessen steric effects and interactions of the chelator–metal complex on peptide–receptor binding affinity. CHX-A″-DTPA-octreotide was radiolabeled with 86Y and evaluated in AR42J tumor bearing male rats. 86Y-CHX-A″-DTPA-octreotide was prepared with high radiochemical yields (> 97 %) and specific activity of 6.49 × 106 MBq/mmole. Somatostatin-receptor mediated uptake was observed in the AR42J tumor (0.94 ± 0.22 % ID/g) in addition to somatostatin receptor expressing organs such as pituitary gland (1.70 ± 0.08 % ID/g), adrenal glands (0.95 ± 0.30 % ID/g), and pancreas (0.65 ± 0.24 % ID/g) [31]. Tumor was clearly visualized at 4 h after injection by PET imaging [31].

In order to quantify the in vivo parameters of 90Y-DOTA-DPhe1-Tyr3-octreotide and the radiation doses delivered to healthy organs, the analogue 86Y-DOTA-DPhe1-Tyr3-octreotide was synthesized and its uptake measured in baboons using PET [18]. 86Y-DOTA-DPhe1-Tyr3-octreotide was further evaluated in a Phase I clinical study involving 24 patients with somatostatin-receptor positive neuroendocrine tumors [15]. Most patients were injected with 370 MBq of 86Y-DOTA-DPhe1-Tyr3-octreotide along with amino acids to reduce renal uptake. PET scans were performed at 4, 24 and 48 h after injection. Primary and metastatic lesions were clearly visualized at 4, 24 and 48 h after injection [15]. In another study comprising 8 patients with progressive metastatic neuroendocrine tumors, 86Y-DOTA-DPhe1-Tyr3-octreotide was compared with 111In-pentetreotide for predicting the radiation doses after 3 cycles of 90Y-DOTA-DPhe1-Tyr3-octreotide [11]. The range of doses (mGy/MBq 90Y-DOTA-Phe1-Tyr3-octreotide) for kidneys, spleen, liver and tumor masses was 0.6–2.8, 1.5–4.2, 0.3–1.3 and 2.1–29.5 (86Y-DOTA-Phe1-Tyr3-octreotide), respectively, versus 1.3–3.0, 1.8–4.4, 0.2–0.8 and 1.4–19.7 (111In-pentetreotide), with wide inter-subject variability. Compared with 86Y-DOTA-Phe1-Tyr3-octreotide, dosimetry with 111In-pentetreotide overestimated doses to kidneys and spleen, whereas the radiation dose to the tumor-free liver was underestimated [11].

86Y labeled peptides targeting the alpha-melanocyte stimulating hormone (alpha-MSH) and gastrin-releasing peptide receptors have also been reported [37,38]. The α-MSH targeted DOTA–ReCCMSH(Arg11) was labeled with 64Cu and 86Y and evaluated in tumor bearing mice [37]. Tumor concentration for both the 86Y- and 64Cu-complexes reached a maximum at 30 min, while co-administering 20 μg of unlabeled complex reduced tumor uptake significantly. Non-target organ concentration was considerably lower with 86Y–DOTA–ReCCMSH(Arg11) than its 64Cu analogue, except in the kidneys, where the 64Cu complex had lower accumulation at all time points [37]. In order to improve specific activity, CHX-A″-DTPA as chelating agent for ReCCMSH(Arg11) was examined due to its rapid and efficient metal chelation properties [39]. CHX-A″-DTPA has been reported to chelate yttrium and other trivalent metal cations nearly instantaneously at a chelator/metal ratio of 1:1 at 22°C, whereas a minimum molar ratio of DOTA-ReCCMSH(Arg11)/radiometal of 20:1 and incubation at ≥75°C were necessary for efficient peptide labeling and therefore post-labeling purification is required [39]. Gastrin-releasing peptide receptors targeted peptide, MP2346 was conjugated with DOTA and radiolabeled with 64Cu and 86Y [38]. 64Cu and 86Y labeled MP2346 were evaluated in mice bearing PC-3 tumor xenografts. Biodistribution in PC3 tumor-bearing mice demonstrated higher tumor uptake, but lower liver retention, in animals injected with 86Y-MP2346 compared to 64Cu-MP2346. It was possible to delineate PC-3 tumors in vivo with 64Cu-MP2346, but superior 86Y-MP2346-PET images were obtained due to lower uptake in clearance organs and lower background activity and therefore the 86Y analogue demonstrated superior targeting characteristics than 64Cu analogue [38]. The studies with α-MSH and gastrin-releasing peptide receptors targeted peptides demonstrated the superiority of 86Y labeled over 64Cu labeled peptides.

86Y labeled antibodies

Numerous 90Y labeled intact monoclonal antibodies were evaluated in pre-clinical and clinical settings [7,4043]. Of the numerous 90Y labeled mAbs evaluated, 90Y-ibritumomab tiuxetan (Zevalin®) was approved by the US FDA in 2002 for treatment of patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma (NHL), including patients with rituximab refractory follicular NHL[43]. Since then many antibodies and proteins have been labeled with 86Y for PET imaging and dosimetry of counterpart 90Y labeled antibodies and proteins [16,22,44]. Human epidermal growth factor 2 (HER2) targeted intact IgG1 mAb, Trastuzumab (Herceptin®) was approved by US FDA in 1999 for treatment of cancer [43].

1B4M-DTPA-trastuzumab was radiolabeled with 86Y and 111In, and evaluated in LS-174T tumor bearing athymic mice [22]. The biodistribution study revealed that 111In-1B4M-DTPA-trastuzumab, while a suitable surrogate for 90Y in the major organs, did not parallel the uptake of 86Y-1B4M-DTPA-trastuzumab in the bone, and thus may not accurately predict the level of 90Y accumulation in the bone for clinical radioimmunotherapy applications [22]. Examination of the results for the uptake of the two radiolabeled antibodies at the bone over time revealed that 111In-1B4M-DTPA-trastuzumab reached a maximum of 2.15 ± 0.49 %ID/g at 12 h and remained constant until 72 h. The amount of radioactivity in the bone declined thereafter at 120 h to 1.07 ± 0.41 %ID/g. On the contrary, accumulation of 86Y-1B4M-DTPA-trastuzumab in the bone was observed over a period of 120 h. The level of 86Y-1B4M-DTPA-trastuzumab at 12 h was higher than 111In-1B4M-DTPA-trastuzumab (2.69 ± 0.71 %ID/g, p = 0.345), however the differences were not found to be significant. This trend continued until the 72 h time point when a marked increase in the 86Y-1B4M-DTPA-trastuzumab level was noted (3.07 ± 0.63% ID/g versus 1.83 ± 0.19 %ID/g; 86Y versus 111In, p = 0.019), which was a significant difference. Finally, the level of 86Y in the bone at the 120 h time point continued to increase from being merely 25% greater than the comparable 111In value at 72 h to 331% greater than the comparable 111In value at 120 h. This study once again exemplified the requirement of employing appropriate matched pair isotopes for imaging and therapy to insure that dosimetry considerations may be addressed accurately [22].

86Y-trastuzumab was further evaluated in mice bearing intraperitoneal ovarian (SKOV-3) and colorectal (LS-174T) tumors [35,45]. Both these studies demonstrated the utility of 86Y-trastuzumab as a PET surrogate for 90Y-trastuzumab distribution. 86Y-trastuzumab localized to sites of disease with minimal normal organ uptake as revealed in microPET and MRI data (Figure 3) [35,45]. Dosimetry calculations with 86Y-trastuzumab in intraperitoneal ovarian carcinoma model revealed the absorbed dose to the kidneys was 0.31 Gy/MBq for 90Y-trastuzumab [35]. The liver received 0.48 Gy/MBq, and the spleen received 0.56 Gy/MBq and the absorbed dose to tumors varied from 0.10 Gy/MBq for radius = 0.1 mm to 3.7 Gy/MBq for radius = 5 mm [35]. Cetuximab (Erbitux®), panitumumab (Vectibix®) and bevacizumab (Avastin®) are other mAbs that are approved by the US FDA for treatment of cancer. Cetuximab and panitumumab target HER1, whereas bevacizumab targets vascular endothelial growth factor (VEGF). All these mAbs have been radiolabeled with 86Y and evaluated in pre-clinical models [16,17,46].

Figure 3
PET maximum intensity projections (3 d p.i.) of female athymic mouse bearing (A) subcutaneous LS-174T and (B) intraperitoneal LS-174T tumors injected with 86Y-CHX-A″-DTPA-trastuzumab. (C) MRI of the female athymic mouse bearing intraperitoneal ...

86Y-CHX-A″-DTPA-panitumumab was developed as a noninvasive molecular imaging tool for selecting patients for HER1-targeted panitumumab therapy and for dosimetry assessment for possible targeted 90Y therapy [16]. Panitumumab was modified with the CHX-A″-DTPA at a 10:1 molar excess of chelate to protein, yielding a final chelate-to-protein ratio of 1.6 chelate molecules per protein molecule. The 86Y-CHX-A″-DTPA-panitumumab conjugate was successfully prepared, with the radiochemical yields ranging from 60% to 75% and specific activity exceeding 2 GBq/mg [16]. Biodistribution, non-compartmental pharmacokinetics, and imaging data revealed HER1-mediated uptake of 86Y-CHX-A″-DTPA-panitumumab and accumulation in HER1-expressing tumor xenografts [16]. Similarly, 86Y-CHX-A″-DTPA-bevacizumab was developed as a potential PET imaging agent of VEGF-A mediated tumor angiogenesis and as a surrogate marker for 90Y-based radioimmunotherapy [17]. In vivo biodistribution and PET imaging studies were performed on mice bearing VEGF-A–secreting human colorectal (LS-174T), human ovarian (SKOV-3) and VEGF-A–negative human mesothelioma (MSTO-211H) xenografts. Biodistribution and PET imaging studies demonstrated highly specific tumor uptake of the radioimmunoconjugate. In mice bearing VEGF-A–secreting LS-174T, SKOV-3 and VEGF-A–negative MSTO-211H tumors, the tumor uptake at 3 days post-injection was 13.6 ± 1.5, 17.4 ± 1.7 and 6.8 ± 0.7 % ID/g, respectively [17]. The corresponding tumor uptake in mice co-injected with 0.05 mg cold bevacizumab were 5.8 ± 1.3, 8.9 ± 1.9 and 7.4 ± 1.0 % ID/g, respectively at the same time point, demonstrating specific blockage of the target in VEGF-A–secreting tumors. The LS-174T and SKOV3 tumors were clearly visualized by PET imaging after injecting 1.8–2.0 MBq 86Y-CHX-A″-DTPA-bevacizumab [17].

Human mindin homologue, mindin/RG-1, is expressed in >80% of prostate cancers metastatic to bone or lymph nodes as well as in locally recurrent tumors in androgen-unresponsive patients [47,48]. A fully human antibody, 19G9, was generated against mindin/RG-1 protein and conjugated with CHX-A″-DTPA, and radiolabeled with either 111In, 90Y, or 86Y for in vivo imaging and radionuclide therapy [47]. PET with 86Y-CHX-A″-DTPA-19G9 showed very specific accumulation of the antibody in LNCaP tumor xenografts with clear tumor delineation apparent 4 h after injection [47]. Based on the imaging data with 86Y-CHX-A″-DTPA-19G9 the therapeutic efficacy of 90Y-CHX-A″-DTPA-19G9 was evaluated in mice bearing LNCaP xenografts. A dose-finding study identified a nontoxic therapeutic dose to be approximately 2.7 MBq. Significant antitumor effects were seen with a single administration of radiolabeled antibody to animals bearing 200 to 400 mm3 tumors [47]. To further develop mindin/RG-1-targeted radionuclide therapy, 19G9 was engineered to obtain the matched diabody, single-chain variable domain (scFv) and novel miniantibody format. The intact antibody, 19G9 and its fragments were conjugated with CHX-A″-DTPA and radiolabeled with 86Y for PET imaging and in vivo evaluation in tumor bearing mice [48].

The size of the construct profoundly affected the pharmacokinetic characteristics of each agent (Figure 4) [48]. The smallest construct (scFv) was rapidly and efficiently extracted from the blood and removed, primarily via the renal system, before significant tumor accumulation. In contrast, the largest construct (IgG) demonstrated prolonged blood retention and significant tumor uptake. PET detected IgG tumor deposition at 24 h. The diabody and miniantibody fragments both demonstrated intermediate blood clearance and tumor localization. Diabody blood levels were rapidly reduced during the initial hours, and tumor deposition was probably not sufficient for radiotherapy. High kidney levels were found for the diabody at 3 and 6 h. PET of the diabody at 48 h did, however, show comparable tumor delineation to that of the IgG and miniantibody [48]. The above studies demonstrate the utility of 86Y labeled antibody not only in understanding the biodistribution of 90Y labeled antibody but also selection of the optimum construct for improved outcomes.

Figure 4
Comparison of PET imaging of 86Y labeled IgG, scFv, diabody and miniantibody construct of 19G9 in tumor bearing mice. Reprinted by permission of the Society of Nuclear Medine from Schneider at al. [48]

Besides antibodies and peptides, there are other reported applications of 86Y. 86Y-citrate was used an analog of the commercially available radiotherapeutic 90Y-citrate [20]. Additionally, a mirror-image oligonucleotide (L-RNA) was radiolabeled with 86Y for PET imaging [49].


Antibodies and peptides function as carriers of cytotoxic substances, such as radioisotopes for treatment of cancer [1,43]. In NHL, anti-CD20 radiolabeled antibodies have superior antitumor activity compared with their unconjugated antibody counterparts, but there is increased, albeit manageable, hematological toxicity if the careful pretreatment planning and dosimetry is performed [7,41]. Similarly, for neuroendocrine and somatostatin receptor expressing tumors, radiolabeled peptides have demonstrated superior antitumor activity than unlabeled peptides [1,6]. However, renal toxicity is a primary concern and therefore careful pretreatment dosimetry and screening is required [8].

For 90Y labeled agents, 86Y offers an attractive alternative to 111In for pretreatment dosimetry and imaging. In pre-clinical studies, the superiority of 86Y over 111In in predicting 90Y has been demonstrated [11,22]. However, 86Y itself has some limitations such as the high-energy gamma-emission and a lack of adequate commercial availability (as compared to 111In). More than 65% of 86Y decays are accompanied by additional gamma-rays with energies from 200 to 3,000 keV that are mostly emitted simultaneously with positron emissions and the subsequent annihilation photons resulting into increased scatter and random events [50,51]. The resulting large number of non-true coincidences evoke a low-frequency background noise that decreases the contrast in reconstructed images and may lead to erroneous quantitation of the 86Y radioactivity concentration in individual regions of interest, thus resulting in false 90Y organ doses [50,51]. Successful attempts have been made to improve the image characteristics of 86Y by developing methods to correct for scatter fractions and spurious coincidences [5052]. Image reconstruction algorithms have been developed, which include models of the statistical nature of nuclear decays and tomography responses that improve the spatial resolution and at the same time reduce the image noise [52,53]. Further advances in instrumentation and image processing may additionally improve spatial resolution and the ability to perform more accurate quantitative analysis with 86Y.

The available choice of radionuclides used for PET imaging of antibodies and peptides are 124I, 64Cu, 89Zr, 86Ga, 18F and 86Y. Each of these radionuclides has their own specific advantage and drawback. For rapidly internalizing antibodies and peptides, 124I will be dehalogenated rapidly in vivo and result in poor tumor to background ratio. 64Cu-TETA-1A3 has previously been reported for clinical PET imaging of metastatic colorectal cancer [54]. Detection of lung and liver metastasis was seriously hindered by non-specific uptake in the liver and the blood due to dissociation of the 64Cu from the currently used chelates for radiolabeling mAbs [54]. 89Zr is an attractive positron emitter due its longer half-life, however preparation of 89Zr labeled mAbs is a multi-step, tedious process and 89Zr has been shown to dissociate from the currently used chelates and to localize in the bone thereafter [55,56]. While for peptides and antibody fragments, 68Ga has gained immense popularity in the recent years [5759], despite the lack of the availability of radiopharmaceutical grade 86Ge/68Ga generator remains an issue (at least in the United States). Clinical translation of all these unconventional radionuclides will largely depend on the commercial availability and supply of radiopharmaceutical grade radionuclide. Availability and high energy gamma emission poses the biggest challenge for clinical translation of 86Y.

It is clear from the selected examples cited in this report that efforts are continuing to develop 86Y labeled radiopharmaceuticals as PET imaging agents and for dosimetry of 90Y labeled radiopharmaceuticals. 86Y labeled radiopharmaceuticals hold significant promises, but several scientific and non-scientific challenges such as availability have to be conquered before realizing its true potential in PET imaging agents and as a surrogate radioisotope for dosimetry of 90Y.


This report was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research, and the United States Department of Health and Human Services. Gratitude is expressed to Prof. Hari Seldon for useful discussion.

List of abbreviations

Monoclonal antibodies
Positron emission tomography
Magnetic resonance imaging
Ethylenediaminetetraacetic acid
Diethylenetriamine pentaacetic acid
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
Cyclic anhydride
% ID/g
Percent injected dose per gram
Alpha-melanocyte stimulating hormone
Non-Hodgkin’s lymphoma
Human epidermal growth factor
Vascular endothelial growth factor
Single-chain variable domain antibody fragment


Conflict of Interest: Herceptin® and Avastin® discussed in the article are manufactured by F. Hoffmann-La Roche, Ltd. TN is an employee of F. Hoffmann-La Roche, Ltd.


1. Krenning EP, Kwekkeboom DJ, Valkema R, Pauwels S, Kvols LK, De Jong M. Peptide receptor radionuclide therapy. Ann NY Acad Sci. 2004;1014:234–245. [PubMed]
2. Sharkey RM, Goldenberg DM. Advances in radioimmunotherapy in the age of molecular engineering and pretargeting. Cancer Invest. 2006;24:82–97. [PubMed]
3. Zinzani PL, Rossi G, Franceschetti S, Botto B, Di Rocco A, Cabras MG, Petti MC, Stefoni V, Broccoli A, Fanti S, Pellegrini C, Montini GC, Gandolfi L, Derenzini E, Argnani L, Fina M, Tucci A, Bottelli C, Pileri S, Baccarani M. Phase ii trial of short-course r-chop followed by 90Y-ibritumomab tiuxetan in previously untreated high-risk elderly diffuse large b-cell lymphoma patients. Clin Cancer Res. 2010;16:3998–4004. [PubMed]
4. Richman CM, DeNardo SJ. Systemic radiotherapy in metastatic breast cancer using 90Y-linked monoclonal muc-1 antibodies. Crit Rev Oncol Hematol. 2001;38:25–35. [PubMed]
5. Wong JY, Chu DZ, Williams LE, Liu A, Zhan J, Yamauchi DM, Wilczynski S, Wu AM, Yazaki PJ, Shively JE, Leong L, Raubitschek AA. A phase I trial of 90Y-dota-anti-cea chimeric t84.66 (ct84.66) radioimmunotherapy in patients with metastatic cea-producing malignancies. Cancer Biother Radiopharm. 2006;21:88–100. [PubMed]
6. Bodei L, Cremonesi M, Grana C, Rocca P, Bartolomei M, Chinol M, Paganelli G. Receptor radionuclide therapy with 90Y-[dota]0-tyr3-octreotide (90Y-dotatoc) in neuroendocrine tumours. Eur J Nucl Med Mol Imag. 2004;31:1038–1046. [PubMed]
7. Wiseman GA, White CA, Stabin M, Dunn WL, Erwin W, Dahlbom M, Raubitschek A, Karvelis K, Schultheiss T, Witzig TE, Belanger R, Spies S, Silverman DH, Berlfein JR, Ding E, Grillo-Lopez AJ. Phase i/ii 90Y-zevalin (Yttrium-90 ibritumomab tiuxetan, idec-y2b8) radioimmunotherapy dosimetry results in relapsed or refractory non-hodgkin’s lymphoma. Eur J Nucl Med. 2000;27:766–777. [PubMed]
8. Bodei L, Cremonesi M, Ferrari M, Pacifici M, Grana CM, Bartolomei M, Baio SM, Sansovini M, Paganelli G. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-dotatoc and 177Lu-dotatate: The role of associated risk factors. Eur J Nucl Med Mol Imag. 2008;35:1847–1856. [PubMed]
9. Mansberg R, Sorensen N, Mansberg V, Van der Wall H. Yttrium-90 bremsstrahlung spect/ct scan demonstrating areas of tracer/tumour uptake. Eur J Nucl Med Mol Imag. 2007;34:1887. [PubMed]
10. Shen S, DeNardo GL, DeNardo SJ. Quantitative bremsstrahlung imaging of Yttrium-90 using a wiener filter. Med Phys. 1994;21:1409–1417. [PubMed]
11. Helisch A, Forster GJ, Reber H, Buchholz HG, Arnold R, Goke B, Weber MM, Wiedenmann B, Pauwels S, Haus U, Bouterfa H, Bartenstein P. Pre-therapeutic dosimetry and biodistribution of 86 Y-dota-phe1-tyr3-octreotide versus 111In-pentetreotide in patients with advanced neuroendocrine tumours. Eur J Nucl Med Mol Imag. 2004;31:1386–1392. [PubMed]
12. Verel I, Visser GW, Boellaard R, Boerman OC, van Eerd J, Snow GB, Lammertsma AA, van Dongen GA. Quantitative 89Zr immuno-pet for in vivo scouting of 90Y-labeled monoclonal antibodies in xenograft-bearing nude mice. J Nucl Med. 2003;44:1663–1670. [PubMed]
13. Lovqvist A, Humm JL, Sheikh A, Finn RD, Koziorowski J, Ruan S, Pentlow KS, Jungbluth A, Welt S, Lee FT, Brechbiel MW, Larson SM. PET imaging of 86Y-labeled anti-lewis y monoclonal antibodies in a nude mouse model: Comparison between 86Y and 111In radiolabels. J Nucl Med. 2001;42:1281–1287. [PubMed]
14. O’Donnell RT, DeNardo SJ, Yuan A, Shen S, Richman CM, Lara PN, Griffith IJ, Goldstein DS, Kukis DL, Martinez GS, Mirick GR, DeNardo GL, Meyers FJ. Radioimmunotherapy with 111In/90Y-2it-bad-m170 for metastatic prostate cancer. Clin Cancer Res. 2001;7:1561–1568. [PubMed]
15. Jamar F, Barone R, Mathieu I, Walrand S, Labar D, Carlier P, de Camps J, Schran H, Chen T, Smith MC, Bouterfa H, Valkema R, Krenning EP, Kvols LK, Pauwels S. 86Y-dota0)-d-phe1-tyr3-octreotide (smt487)--a phase 1 clinical study: Pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion. Eur J Nucl Med Mol Imag. 2003;30:510–518. [PubMed]
16. Nayak TK, Garmestani K, Baidoo KE, Milenic DE, Brechbiel MW. Preparation, biological evaluation, and pharmacokinetics of the human anti-her1 monoclonal antibody panitumumab labeled with 86 Y for quantitative PET of carcinoma. J Nucl Med. 2010;51:942–950. [PMC free article] [PubMed]
17. Nayak TK, Garmestani K, Baidoo KE, Milenic DE, Brechbiel MW. PET imaging of tumor angiogenesis in mice with vegf-a-targeted 86Y-chx-a″-dtpa-bevacizumab. Int J Cancer. 2011;128:920–926. [PMC free article] [PubMed]
18. Rosch F, Herzog H, Stolz B, Brockmann J, Kohle M, Muhlensiepen H, Marbach P, Muller-Gartner HW. Uptake kinetics of the somatostatin receptor ligand [86Y]dota-dphe1-tyr3-octreotide ([86Y]smt487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue. Eur J Nucl Med. 1999;26:358–366. [PubMed]
19. Qaim SM. Decay data and production yields of some non-standard positron emitters used in PET. Q J Nucl Med Mol Imag. 2008;52:111–120. [PubMed]
20. Herzog H, Rosch F, Stocklin G, Lueders C, Qaim SM, Feinendegen LE. Measurement of pharmacokinetics of Yttrium-86 radiopharmaceuticals with pet and radiation dose calculation of analogous Yttrium-90 radiotherapeutics. J Nucl Med. 1993;34:2222–2226. [PubMed]
21. Yoo J, Tang L, Perkins TA, Rowland DJ, Laforest R, Lewis JS, Welch MJ. Preparation of high specific activity 86Y using a small biomedical cyclotron. Nucl Med Biol. 2005;32:891–897. [PubMed]
22. Garmestani K, Milenic DE, Plascjak PS, Brechbiel MW. A new and convenient method for purification of 86Y using a Sr(ii) selective resin and comparison of biodistribution of 86Y and 111In labeled herceptin. Nucl Med Biol. 2002;29:599–606. [PubMed]
23. Yoo J, Tang L, Perkins TA, Rowland DJ, Laforest R, Lewis JS, Welch MJ. Preparation of high specific activity 86Y using a small biomedical cyclotron. Nucl Med Biol. 2005;32:891–897. [PubMed]
24. Avila-Rodriguez MA, Nye JA, Nickles RJ. Production and separation of non-carrier-added 86Y from enriched 86Sr targets. Appl Radiat Isot. 2008;66:9–13. [PubMed]
25. Brechbiel MW, Gansow OA. Backbone-substituted dtpa ligands for 90Y radioimmunotherapy. Bioconjugate Chem. 1991;2:187–194. [PubMed]
26. Roselli M, Schlom J, Gansow OA, Raubitschek A, Mirzadeh S, Brechbiel MW, Colcher D. Comparative biodistributions of yttrium- and indium-labeled monoclonal antibody b72.3 in athymic mice bearing human colon carcinoma xenografts. J Nucl Med. 1989;30:672–682. [PubMed]
27. Camera L, Kinuya S, Garmestani K, Brechbiel MW, Wu C, Pai LH, McMurry TJ, Gansow OA, Pastan I, Paik CH, et al. Comparative biodistribution of indium- and yttrium-labeled b3 monoclonal antibody conjugated to either 2-(p-scn-bz)-6-methyl-dtpa (1b4m-dtpa) or 2-(p-scn-bz)-1,4,7,10-tetraazacyclododecane tetraacetic acid (2b-dota) Eur J Nucl Med. 1994;21:640–646. [PubMed]
28. Camera L, Kinuya S, Garmestani K, Wu C, Brechbiel MW, Pai LH, McMurry TJ, Gansow OA, Pastan I, Paik CH, et al. Evaluation of the serum stability and in vivo biodistribution of chx-dtpa and other ligands for yttrium labeling of monoclonal antibodies. J Nucl Med. 1994;35:882–889. [PubMed]
29. Camera L, Kinuya S, Garmestani K, Pai LH, Brechbiel MW, Gansow OA, Paik CH, Pastan I, Carrasquillo JA. Evaluation of a new dtpa-derivative chelator: Comparative biodistribution and imaging studies of 111In-labeled b3 monoclonal antibody in athymic mice bearing human epidermoid carcinoma xenografts. Nucl Med Biol. 1993;20:955–962. [PubMed]
30. Kobayashi H, Wu C, Yoo TM, Sun BF, Drumm D, Pastan I, Paik CH, Gansow OA, Carrasquillo JA, Brechbiel M. W: Evaluation of the in vivo biodistribution of yttrium-labeled isomers of chx-dtpa-conjugated monoclonal antibodies. J Nucl Med. 1998;39:829–836. [PubMed]
31. Clifford T, Boswell CA, Biddlecombe GB, Lewis JS, Brechbiel MW. Validation of a novel chx-a″ derivative suitable for peptide conjugation: Small animal pet/ct imaging using Yttrium-86-chx-a″-octreotide. J Med Chem. 2006;49:4297–4304. [PubMed]
32. Deshpande SV, DeNardo SJ, Kukis DL, Moi MK, McCall MJ, DeNardo GL, Meares CF. Yttrium-90-labeled monoclonal antibody for therapy: Labeling by a new macrocyclic bifunctional chelating agent. J Nucl Med. 1990;31:473–479. [PubMed]
33. Harrison A, Walker CA, Parker D, Jankowski KJ, Cox JP, Craig AS, Sansom JM, Beeley NR, Boyce RA, Chaplin L, et al. The in vivo release of 90Y from cyclic and acyclic ligand-antibody conjugates. Int J Radiat Appl Instrum B. 1991;18:469–476. [PubMed]
34. de Jong M, Bakker WH, Krenning EP, Breeman WA, van der Pluijm ME, Bernard BF, Visser TJ, Jermann E, Behe M, Powell P, Macke HR. Yttrium-90 and Indium-111 labelling, receptor binding and biodistribution of [dota0,d-phe1,tyr3]octreotide, a promising somatostatin analogue for radionuclide therapy. Eur J Nucl Med. 1997;24:368–371. [PubMed]
35. Palm S, Enmon RM, Jr, Matei C, Kolbert KS, Xu S, Zanzonico PB, Finn RL, Koutcher JA, Larson SM, Sgouros G. Pharmacokinetics and biodistribution of 86Y-trastuzumab for 90Y dosimetry in an ovarian carcinoma model: Correlative micropet and mri. J Nucl Med. 2003;44:1148–1155. [PubMed]
36. Brechbiel M. W: Bifunctional chelates for metal nuclides. Q J Nucl Med Mol Imag. 2008;52:166–173. [PMC free article] [PubMed]
37. McQuade P, Miao Y, Yoo J, Quinn TP, Welch MJ, Lewis JS. Imaging of melanoma using 64Cu-and 86Y-dota-reccmsh(arg11), a cyclized peptide analogue of alpha-msh. J Med Chem. 2005;48:2985–2992. [PubMed]
38. Biddlecombe GB, Rogers BE, de Visser M, Parry JJ, de Jong M, Erion JL, Lewis JS. Molecular imaging of gastrin-releasing peptide receptor-positive tumors in mice using 64Cu- and 86Y-dota-(pro1,tyr4)-bombesin(1–14) Bioconjugate Chem. 2007;18:724–730. [PubMed]
39. Wei L, Zhang X, Gallazzi F, Miao Y, Jin X, Brechbiel MW, Xu H, Clifford T, Welch MJ, Lewis JS, Quinn TP. Melanoma imaging using 111In-, 86Y- and 68Ga-labeled chx-a″-re(arg11)ccmsh. Nucl Med Biol. 2009;36:345–354. [PMC free article] [PubMed]
40. Kelly MP, Lee FT, Smyth FE, Brechbiel MW, Scott A. M: Enhanced efficacy of 90Y-radiolabeled anti-lewis y humanized monoclonal antibody hu3s193 and paclitaxel combined-modality radioimmunotherapy in a breast cancer model. J Nucl Med. 2006;47:716–725. [PubMed]
41. Wiseman GA, White CA, Witzig TE, Gordon LI, Emmanouilides C, Raubitschek A, Janakiraman N, Gutheil J, Schilder RJ, Spies S, Silverman DH, Grillo-Lopez AJ. Radioimmunotherapy of relapsed non-hodgkin’s lymphoma with zevalin, a 90Y-labeled anti-cd20 monoclonal antibody. Clin Cancer Res. 1999;5:3281s–3286s. [PubMed]
42. Vallabhajosula S, Goldsmith SJ, Kostakoglu L, Milowsky MI, Nanus DM, Bander NH. Radioimmunotherapy of prostate cancer using 90Y- and 177Lu-labeled j591 monoclonal antibodies: Effect of multiple treatments on myelotoxicity. Clin Cancer Res. 2005;11:7195s–7200s. [PubMed]
43. Boswell CA, Brechbiel M. W: Development of radioimmunotherapeutic and diagnostic antibodies: An inside-out view. Nucl Med Biol. 2007;34:757–778. [PMC free article] [PubMed]
44. Nayak TK, Brechbiel M. W: Radioimmunoimaging with longer-lived positron-emitting radionuclides: Potentials and challenges. Bioconjugate Chem. 2009;20:825–841. [PMC free article] [PubMed]
45. Milenic DE, Wong KJ, Baidoo KE, Nayak TK, Regino CA, Garmestani K, Brechbiel MW. Targeting her2: A report on the in vitro and in vivo pre-clinical data supporting trastuzumab as a radioimmunoconjugate for clinical trials. MAbs. 2010;2:550–564. [PMC free article] [PubMed]
46. Nayak TK, Regino CA, Wong KJ, Milenic DE, Garmestani K, Baidoo KE, Szajek LP, Brechbiel MW. Pet imaging of her1-expressing xenografts in mice with 86Y-chx-a″-dtpa-cetuximab. Eur J Nucl Med Mol Imag. 2010;37:1368–1376. [PMC free article] [PubMed]
47. Parry R, Schneider D, Hudson D, Parkes D, Xuan JA, Newton A, Toy P, Lin R, Harkins R, Alicke B, Biroc S, Kretschmer PJ, Halks-Miller M, Klocker H, Zhu Y, Larsen B, Cobb RR, Bringmann P, Roth G, Lewis JS, Dinter H, Parry G. Identification of a novel prostate tumor target, mindin/rg-1 for antibody-based radiotherapy of prostate cancer. Cancer Res. 2005;65:8397–8405. [PubMed]
48. Schneider DW, Heitner T, Alicke B, Light DR, McLean K, Satozawa N, Parry G, Yoo J, Lewis JS, Parry R. In vivo biodistribution, pet imaging, and tumor accumulation of 86Y- and 111In-antimindin/rg-1, engineered antibody fragments in lncap tumor-bearing nude mice. J Nucl Med. 2009;50:435–443. [PubMed]
49. Schlesinger J, Koezle I, Bergmann R, Tamburini S, Bolzati C, Tisato F, Noll B, Klussmann S, Vonhoff S, Wuest F, Pietzsch HJ, Steinbach J. An 86Y-labeled mirror-image oligonucleotide: Influence of Y-DOTA isomers on the biodistribution in rats. Bioconjugate Chem. 2008;19:928–939. [PubMed]
50. Vandenberghe S. Three-dimensional positron emission tomography imaging with 124I and 86Y. Nucl Med Commun. 2006;27:237–245. [PubMed]
51. Herzog H, Tellmann L, Scholten B, Coenen HH, Qaim SM. Pet imaging problems with the nonstandard positron emitters yttrium-86 and iodine-124. Q J Nucl Med Mol Imag. 2008;52:159–165. [PubMed]
52. Buchholz HG, Herzog H, Forster GJ, Reber H, Nickel O, Rosch F, Bartenstein P. Pet imaging with yttrium-86: Comparison of phantom measurements acquired with different pet scanners before and after applying background subtraction. Eur J Nucl Med Mol Imag. 2003;30:716–720. [PubMed]
53. Liu X, Laforest R. Quantitative small animal pet imaging with nonconventional nuclides. Nucl Med Biol. 2009;36:551–559. [PubMed]
54. Philpott GW, Schwarz SW, Anderson CJ, Dehdashti F, Connett JM, Zinn KR, Meares CF, Cutler PD, Welch MJ, Siegel BA. Radioimmunopet: Detection of colorectal carcinoma with positron-emitting copper-64-labeled monoclonal antibody. J Nucl Med. 1995;36:1818–1824. [PubMed]
55. Verel I, Visser GW, Boellaard R, Stigter-van Walsum M, Snow GB, van Dongen GA. 89Zr immuno-pet: Comprehensive procedures for the production of 89Zr-labeled monoclonal antibodies. J Nucl Med. 2003;44:1271–1281. [PubMed]
56. Meijs WE, Haisma HJ, Van der Schors R, Wijbrandts R, Van den Oever K, Klok RP, Pinedo HM, Herscheid JD. A facile method for the labeling of proteins with zirconium isotopes. Nucl Med Biol. 1996;23:439–448. [PubMed]
57. Antunes P, Ginj M, Zhang H, Waser B, Baum RP, Reubi JC, Maecke H. Are radiogallium-labelled dota-conjugated somatostatin analogues superior to those labelled with other radiometals? Eur J Nucl Med Mol Imaging. 2007;34:982–993. [PubMed]
58. Srirajaskanthan R, Kayani I, Quigley AM, Soh J, Caplin ME, Bomanji J. The role of 68Ga-DOTATATE PET in patients with neuroendocrine tumors and negative or equivocal findings on 111In-DTPA-octreotide scintigraphy. J Nucl Med. 2010;51:875–882. [PubMed]
59. Smith-Jones PM, Solit DB, Akhurst T, Afroze F, Rosen N, Larson SM. Imaging the pharmacodynamics of HER2 degradation in response to hsp90 inhibitors. Nature Biotech. 2004;22:701–706. [PubMed]