Auger electron (AE) therapy is expected to be especially efficient for metastatic disease due to the highly localized energy deposition of AE-emitters. Lanthanum-135 (135La) has been proposed as a candidate for AE therapy since it has beneficial radiochemical characteristics and a high AE yield. In this proof-of-principle study, we investigated internalizing (DOTA-TATE) and non-internalizing (DOTA-LM3) SSTR2 vectors labeled with 135La in the in vitro CA20948 model for neuroendocrine tumors. Reproducible and traceable activity measurements were challenging due to extensive non-linearity and measurement geometry effects, which was attributed to a substantial low-energy X-ray yield of 135La. The maximum molar activity that could be achieved was 50 MBq/nmol with a radiochemical conversion and purity of > 99

Abstract Background Phenanthroline derivatives are well-known chelators in coordination chemistry, but their potential in the rapidly evolving field of targeted radionuclide therapy (TRT) has not yet been explored. In TRT, DOTA remains the gold standard chelator for several clinically relevant radionuclides such as terbium-161, lutetium-177 and bismuth-213. However, its requirement for elevated labeling temperatures is a drawback, particularly for heat-sensitive targeting vectors. Although several alternative chelators have been reported in recent years, there remains an interest in new systems with suitable complexation properties. In this work, we evaluate whether phenanthroline-based ligands can serve as useful chelators in TRT, using the octadentate chelator H4FENTA and a newly developed bifunctional analog, BF-FENTA. Their ability to complex [161Tb]Tb3+, [177Lu]Lu3+, and [213Bi]Bi3+, as well as their kinetic inertness, was assessed and compared to the benchmark chelators DOTA and CHX-A”-DTPA. Results BF-FENTA was prepared via mono-substitution of 2,9-bis(chloromethyl)-1,10-phenanthroline with di-tert-butyl iminodiacetate, followed by a second substitution with the bifunctional arm. Both H4FENTA and BF-FENTA efficiently incorporated [161Tb]Tb3+ under mild conditions within 15 min at an apparent molar activity (AMA) of 150 MBq/nmol. Stability studies showed that both chelators formed an unstable complex with [161Tb]Tb3+, while the [177Lu]Lu3+ chelates showed similar stability compared to DOTA after 7 days in human serum. However, a DTPA challenge indicated a reduced kinetic inertness for both FENTA chelators compared to DOTA. For [213Bi]Bi3+, rapid incorporation was observed with the phenanthroline chelators, with H4FENTA achieving high radiochemical conversions (> 90%) at high AMAs of up to ~ 200 MBq/nmol after 5 min. Additionally, H4FENTA displayed a high selectivity for [213Bi]Bi3+ in the presence of competing metal ions. BF-FENTA showed slightly less favorable chelation properties with [213Bi]Bi3+ compared to H4FENTA. Nonetheless, the [213Bi]Bi3+ complexes remained intact in both buffer (NH4OAc, pH 6.0) and human serum after 90 min. Conclusion Both H4FENTA and BF-FENTA rapidly incorporated terbium-161, lutetium-177, and bismuth-213. While the kinetic inertness of their terbium-161 and lutetium-177 complexes was inadequate, H4FENTA exhibited favorable kinetic inertness with bismuth-213 over the 90 min timeframe, identifying it as a promising chelator. In contrast, further structural refinement is needed for its bifunctional analog.

Recent data on 161Tb-labeled radiopharmaceuticals indicate a benefit in treatment efficacy due to the emission of high-energy Auger and conversion electrons in addition to β particles. We aimed to investigate differences in therapeutic potential of the gastrin-releasing peptide receptor (GRPR) antagonists RM2 (DOTA-Pip5-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) and AMTG (DOTA-Pip5-D-Phe6-Gln7-α-Me-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) radiolabeled with 161Tb and 177Lu in PC-3 tumor-bearing mice. We hypothesized that the superior in vivo stability of AMTG in combination with 161Tb would result in improved tumor control and overall survival as compared to RM2 and 177Lu counterparts. Treatment studies in PC-3 tumor-bearing Nu/J mice were initiated once tumor volume was 100 mm3. 161Tb- and 177Lu-Labeling was completed at 90 °C within 10 min (1.0 M sodium acetate buffer, pH = 5.5, molar activity of 50 MBq/nmol). Radiolabeled GRPR ligands were administered in treatment (PC-3 tumor-bearing, n = 6–7 per group) and toxicity (healthy animals, n = 3 per group) animals on day 0 and day 7 of the experiment ( 15 MBq each). Treatment animals were sacrificed once tumor volume surpassed 1,500 mm3. Toxicity animals were sacrificed 45 d after injection and analyzed for complete blood count and metabolic panel. Animals were assigned to five groups (control, [177Lu]Lu-RM2, [177Lu]Lu-AMTG, [161Tb]Tb-RM2, [161Tb]Tb-AMTG). Each treatment group received a total activity amount of 26–31 MBq of the respective radiolabeled compound. All treatments resulted in improved tumor control and overall survival related to vehicle animals. [161Tb]Tb-AMTG had the longest median overall survival of 58.1 ± 5.4 d after initiation of treatment. No signs of long-term toxicity were observed during this study in any treatment group. The combination of Auger electrons with high in vivo stability of [161Tb]Tb-AMTG resulted in substantially improved tumor control and overall survival in PC-3 tumor-bearing mice, thus expanding the therapeutic potential of GRPR antagonists in GRPR-expressing malignancies.

Targeted radioligand therapy (RLT) and radioimmunotherapy (RIT) have emerged as effective and safe treatment modalities for metastatic cancers. Nectin-4 is a Ca2+-independent immunoglobulin-like cell adhesion molecule. Aberrant expression of Nectin-4 is observed in many cancers notably TNBC and NSCLC. No RLT/RIT is approved/in advanced clinical development against TNBC and NSCLC. For the first time, we report the efficacy and safety of 161Tb-labeled anti-Nectin-4 antibody ([161Tb]Tb-DOTA-N4MU01) against Nectin-4 positive TNBC and NSCLC mouse models. Nectin-4-expressing mouse syngeneic cell lines for TNBC (4T1.Nectin-4 and E0771.Nectin-4) and NSCLC (LLC.Nectin-4 and CMT167.Nectin-4) were obtained by stable transduction or transfection. Nectin-4 expression and binding affinity of immunoconjugates were assessed by flow cytometry and radioligand binding assays, with internalization studied using live-cell imaging. Pharmacokinetics and safety of the radioligand were evaluated in healthy female Balb/C mice, with tumor uptake assessed by SPECT/CT and biodistribution in tumor-bearing mice. The efficacy of the radioligand was assessed in mouse xenograft models of Nectin-4-expressing human cell line, MDA-MB468, and mouse syngeneic cell lines 4T1.Nectin-4 (immune checkpoint blockade therapy (ICBT) resistant), E0771.Nectin-4, CMT167.Nectin-4, and LLC.Nectin-4. Nectin-4 expression on syngeneic cell lines was high. DOTA conjugation did not affect the internalization of N4MU01 (p ˃ 0.999) while immunoconjugates retained strong binding affinities to human Nectin-4 (≤ 11 nM). 161Tb was stably chelated to DOTA-N4MU01 with yield and purity ˃ 95 %. The clearance half-life of [161Tb]Tb-DOTA-N4MU01 was 120 ± 20 h while a dose of 2x 5 MBq administered intravenously, and 7 d apart was well tolerated over 28 d. Tumor targeting was specific with tumor-to-muscle uptake ratios of 7.7 and 6.7 for CMT167.Nectin-4 and 4T1.Nectin-4 at 24 h post-injection. In 4T1.Nectin-4 model, single dose radioligand at 2.5 MBq and 5 MBq and a repeated dose at 2x 5 MBq showed significant dose-dependent anti-tumor efficacy and survival (p ≤ 0.0021) compared with saline and N4MU01 (25 µg), with 2x 5MBq of radioligand producing complete remission in 20 % of mice. Anti-PD-L1 ICBT had no anti-tumor effect (p = 1166) on this model. A dose of 2x 5 MBq of radioligand resulted in significant anti-tumor effects and survival compared with saline and N4MU01 (25 µg), in aggressive E0771.Nectin-4 (p ≤ 0.0316), CMT167.Nectin-4 (p ≤ 0.0236), LLC.Nectin-4 (p ≤ 0.0097), and MDA-MB-468 (p ≤ 0.0.0017) xenograft models. Our findings reveal the clinical potential of [161Tb]Tb-DOTA-N4MU01 as an effective and safe theranostic against Nectin-4-expressing TNBC and NSCLC, even for patients who do not respond to ICBT Fabrice Ngoh Njotu, Hanan Babeker, Jessica Pougoue Ketchemen, Emmanuel Nwangele, Anjong Tikum, Nikita Henning, He Dong, Nava Hassani, Alissar Monzer, Dede Api Fon, Chrysantus Njobinkir Bimela, Therese Mercado, Franco Vizeacoumar, Dennis Elema, Michiel Van de Voorde, Maarten Ooms, Maruti Chandra Uppalapati, Humphrey Fonge. Preclinical efficacy and safety of [161Tb]Tb-labeled anti-nectin-4 radioimmunoconjugate as theranostic against triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 584.

Actinium-225 (225Ac) based targeted alpha therapies (TAT) have emerged as a promising strategy for the treatment of several cancer types due to its favourable decay properties, including high linear energy transfer and short particle range, which enable precise tumour targeting. However, there are limited bifunctional chelators (BFCs) available for 225Ac. In this study, we aim to evaluate the potential of DEPA-based chelators for 225Ac-labelling. The BFCs 3p-C-DEPA-NO2, 3p-C-DEPA-NCS, and 3p-C-DEPA-TFP-PEG4 were synthesized with high yield (≥ 86

Strategies that focus on delivering Auger electron emitters to highly radiosensitive intracellular targets—such as the nucleus, cell membrane, or mitochondria—are gaining attention. Targeting these organelles could enhance therapeutic efficacy while minimizing off-target toxicity by allowing lower administered doses. In this context, this study explores the therapeutic potential of 161Tb-labeled radiocomplexes that integrate the mitochondria-targeting triphenylphosphonium (TPP) moiety with a prostate-specific membrane antigen (PSMA) targeting vector. The goal is to assess these dual-targeted radiocomplexes for their ability to deliver conversion electrons (CE) and Auger electrons (AEs) to prostate cancer (PCa) cells, specifically targeting the mitochondria to enhance therapeutic efficacy. Two novel radiocomplexes, [161Tb]Tb-TPP-PSMA and [161Tb]Tb-TPP-G3-PSMA, were synthesized with high radiochemical yield and purity. The proposed structures were validated using HPLC and ESI-MS analysis, with their natTb counterparts serving as reference compounds. In vitro experiments included cellular uptake, internalization, mitochondrial uptake, and DNA damage assays in PSMA-positive PCa cell lines. Clonogenic assays were performed to evaluate cell survival post-treatment. In vivo studies were conducted using SCID/Beige mice bearing PCa xenografts and involved µSPECT/CT imaging and radiometabolite analysis to evaluate biodistribution, pharmacokinetics, tumor uptake and in vivo stability of the radiocomplexes. Both [161Tb]Tb-TPP-PSMA and [161Tb]Tb-TPP-G3-PSMA showed high radiochemical stability and were efficiently internalized by PSMA-positive cells, while showing minimal uptake in PSMA-negative cells. These dual-targeted radiocomplexes demonstrated significantly higher mitochondrial uptake compared to the non-TPP-containing [161Tb]Tb-PSMA-617, leading to increased DNA damage and enhanced radiocytotoxicity. In vivo, the dual-targeted complexes demonstrated PSMA-specific tumor uptake and pharmacokinetics comparable to [161Tb]Tb-PSMA-617, with effective clearance from non-target tissues. The TPP-modified 161Tb-radiocomplexes effectively targeted the mitochondria of PSMA-positive PCa cells, leading to increased DNA damage and reduced cell viability compared to single-targeted radiocomplexes. These findings suggest that dual-targeting strategies, which combine PSMA and mitochondrial targeting, can enhance the therapeutic potential of radiopharmaceuticals for prostate cancer treatment.

The growing availability of new radiometals with favorable decay properties for cancer diagnosis and therapy highlights the need for chelators that can stably bind a variety of metal ions. 1-Hydroxy-2(1H)-pyridinones (1,2-HOPOs) are effective bidentate ligands with strong affinity for trivalent and tetravalent metals. In this study, we developed a bifunctional octadentate 1,2-HOPO chelator with a methyl tetrazine (Me-Tz) moiety, HOPO-O8-Me-Tz, and evaluated its coordination to [89Zr]Zr4+, [161Tb]Tb3+, and [227Th]Th4+ for theranostic applications. HOPO-O8-Me-Tz was conjugated to HER2/neu targeting antibody Trastuzumab (Tmab), modified with transcyclooctene (TCO), using the inverse electron demand Diels-Alder (IEDDA) click reaction to yield HOPO-O8-Tmab. Radiolabeled conjugates were synthesized under mild conditions (30 min, ambient temperature) and evaluated in vitro and in vivo in SKOV-3 tumour-bearing nude mice. All radiometal complexes demonstrated high stability in serum over 7 days. In vivo, [89Zr]Zr-, [161Tb]Tb- and [227Th]Th-HOPO-O8-Tmab showed high tumour uptake (9.87 ± 3.57, 11.29 ± 4.14 and 19.40 ± 5.40 %ID/g, respectively). Notably, [161Tb]Tb- and [227Th]Th-conjugates exhibited low bone uptake at 96 h post-injection, indicating excellent in vivo stability. The potential redistribution of the alpha-emitting daughter nuclide [223Ra]Ra2+ from [227Th]Th-HOPO-O8-Tmab was assessed, revealing elevated 223Ra in the bone and joint. These findings underscore the promise of HOPO-O8-Me-Tz as a versatile bifunctional chelator for next-generation theranostic radioimmunoconjugates, while also highlighting the importance of managing daughter radionuclide redistribution in alpha therapy.

In this study, we present the first reported use of bioorthogonal click chemistry with rhenium-188 for radiolabelling of an anti-c-Met VHH Nanobody (R). We employed a "chelate-then-click" strategy, wherein a bifunctional chelator was designed in two parts, which were subsequently joined post-labelling and post-conjugation via the strain-promoted azide-alkyne cycloaddition (SPAAC) reaction. Cysteine-selective conjugation of the VHH was achieved through thiol-Michael addition, forming a VHH-DBCO construct. Radiolabelling of the azide-functionalised chelator with [188Re]Re(v) was optimised to achieve a radiochemical conversion of similar to 70%, despite challenges associated with maintaining the azide functionality under reducing conditions. The final product, [188Re]Re-VHH, demonstrated high radiochemical purity and good in vitro stability over 48 h. In vitro cell-binding studies against U87MG and BxPC3 cell lines proved the retention of c-Met binding post-labelling. In vivo biodistribution studies on mice bearing BxPC3 tumour xenografts, however, exhibited suboptimal tumour uptake, likely a result of the low molar activity (1.4-3.3 MBq nmol-1) of the radioconjugate. This work illustrates the potential of bioorthogonal click chemistry for radiolabelling biomolecules with 188Re, although further optimisation or alternative radiolabelling strategies to enhance the molar activity are necessary to improve pharmacokinetics.

Ovarian cancer is the most common gynecological malignancy worldwide with the highest mortality. This low survival rate can be attributed to the fact that symptoms arise only at an advanced disease stage, characterized by a (micro)metastatic spread across the peritoneal cavity. Radiopharmaceuticals, composed of a targeting moiety coupled with either a diagnostic or therapeutic radionuclide, constitute a relatively underexplored theranostic approach that may improve the current standard of care. Efficient patient stratification, follow-up and treatment are several caveats that could be addressed with theranostics to improve patient outcomes. So far, the bulk of research is situated and often halted at the preclinical level, employing murine models of primary and metastatic peritoneal disease that do not necessarily provide an accurate representation of the disease heterogeneity, (intrinsic) drug resistance or the complex physiological interactions with the tumor microenvironment. Radioimmunoconjugates with therapeutic α- and electron-emitting radionuclides have been the prevailing standard, targeting a myriad of cell-membrane markers that are expressed in the various heterogeneous histological subtypes of ovarian cancer. Evidently, several hurdles exist within preclinical research that are potentially withholding these agents from advancing into clinical practice. On the other hand, the field of nuclear medicine has also seen significant innovation to address shortcomings related to target/ligand identification, preclinical research models, radiochemistry, radiopharmacy and dosimetry, as outlined in this review. Altogether, theranostics hold great promise to answer an unmet medical need for ovarian cancer.

Terbium features four clinically interesting radionuclides for application in nuclear medicine: terbium-149, terbium-152, terbium-155, and terbium-161.Their identical chemical properties enable the synthesis of radiopharmaceuticals with the same pharmacokinetic character, while their distinctive decay characteristics make them valuable for both imaging and therapeutic applications.In particular, terbium-152 and terbium-155 are useful candidates for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, respectively; whereas terbium-149 and terbium-161 find application in α-and β --/Auger electron therapy, respectively.This unique characteristic makes the terbium family ideal for the "matched-pair" principle of theranostics.In this review, the advantages and challenges of terbium-based radiopharmaceuticals are discussed, covering the entire chain from radionuclide production to bedside administration.It elaborates on the fundamental properties of terbium, the production routes of the four interesting radionuclides and gives an overview of the available bifunctional chelators.Finally, we discuss the preclinical and clinical studies as well as the prospects of this promising development in nuclear medicine.

BackgroundTargeted radionuclide therapy is established as a highly effective strategy for the treatment of metastatic tumors; however, the co-development of suitable imaging companions to therapy remains significant challenge. Theranostic isotopes of terbium (149Tb, 152Tb, 155Tb, 161Tb) have the potential to provide chemically identical radionuclidic pairs, which collectively encompass all modes of nuclear decay relevant to nuclear medicine. Herein, we report the first radiochemistry and preclinical studies involving 155Tb- and 161Tb-labeled crown-αMSH, a small peptide-based bioconjugate suitable for targeting melanoma.Methods155Tb was produced via proton induced spallation of Ta targets using the isotope separation and acceleration facility at TRIUMF with isotope separation on-line (ISAC/ISOL). The radiolabeling characteristics of crown-αMSH with 155Tb and/or 161Tb were evaluated by concentration-dependence radiolabeling studies, and radio-HPLC stability studies. LogD7.4 measurements were obtained for [161Tb]Tb-crown-αMSH. Competitive binding assays were undertaken to determine the inhibition constant for [natTb]Tb-crown-αMSH in B16-F10 cells. Pre-clinical biodistribution and SPECT/CT imaging studies of 155Tb and 161Tb labeled crown-αMSH were undertaken in male C57Bl/6 J mice bearing B16-F10 melanoma tumors to evaluate tumor specific uptake and imaging potential for each radionuclide.ResultsQuantitative radiolabeling of crown-αMSH with [155Tb]Tb3+ and [161Tb]Tb3+ was demonstrated under mild conditions (RT, 10 min) and low chelator concentrations; achieving high molar activities (23–29 MBq/nmol). Radio-HPLC studies showed [161Tb]Tb-crown-αMSH maintains excellent radiochemical purity in human serum, while gradual metabolic degradation is observed in mouse serum. Competitive binding assays showed the high affinity of [natTb]Tb-crown-αMSH toward MC1R. Two different methods for preparation of the [155Tb]Tb-crown-αMSH radiotracer were investigated and the impacts on the biodistribution profile in tumor bearing mice is compared. Preclinical in vivo studies of 155Tb- and 161Tb- labeled crown-αMSH were performed in parallel, in mice bearing B16-F10 tumors; where the biodistribution results showed similar tumor specific uptake (6.06–7.44 %IA/g at 2 h pi) and very low uptake in nontarget organs. These results were further corroborated through a series of single-photon emission computed tomography (SPECT) studies, with [155Tb]Tb-crown-αMSH and [161Tb]Tb-crown-αMSH showing comparable uptake profiles and excellent image contrast.ConclusionsCollectively, our studies highlight the promising characteristics of [155Tb]Tb-crown-αMSH and [161Tb]Tb-crown-αMSH as theranostic pair for nuclear imaging (155Tb) and radionuclide therapy (161Tb).

Abstract Background Element-equivalent matched theranostic pairs facilitate quantitative in vivo imaging to establish pharmacokinetics and dosimetry estimates in the development of preclinical radiopharmaceuticals. Terbium radionuclides have significant potential as matched theranostic pairs for multipurpose applications in nuclear medicine. In particular, 155Tb (t1/2 = 5.32 d) and 161Tb (t1/2 = 6.89 d) have been proposed as a theranostic pair for their respective applications in single photon emission computed tomography (SPECT) imaging and targeted beta therapy. Our study assessed the performance of preclinical quantitative SPECT imaging with 155Tb and 161Tb. A hot rod resolution phantom with rod diameters ranging between 0.85 and 1.70 mm was filled with either 155Tb (21.8 ± 1.7 MBq/mL) or 161Tb (23.6 ± 1.9 MBq/mL) and scanned with the VECTor preclinical SPECT/CT scanner. Image performance was evaluated with two collimators: a high energy ultra high resolution (HEUHR) collimator and an extra ultra high sensitivity (UHS) collimator. SPECT images were reconstructed from photopeaks at 43.0 keV, 86.6 keV, and 105.3 keV for 155Tb and 48.9 keV and 74.6 keV for 161Tb. Quantitative SPECT images of the resolution phantoms were analyzed to report inter-rod contrast, recovery coefficients, and contrast-to-noise metrics. Results Quantitative SPECT images of the resolution phantom established that the HEUHR collimator resolved all rods for 155Tb and 161Tb, and the UHS collimator resolved rods ≥ 1.10 mm for 161Tb and ≥ 1.30 mm for 155Tb. The HEUHR collimator maintained better quantitative accuracy than the UHS collimator with recovery coefficients up to 92%. Contrast-to-noise metrics were also superior with the HEUHR collimator. Conclusions Both 155Tb and 161Tb demonstrated potential for applications in preclinical quantitative SPECT imaging. The high-resolution collimator achieves < 0.85 mm resolution and maintains quantitative accuracy in small volumes which is advantageous for assessing sub organ activity distributions in small animals. This imaging method can provide critical quantitative information for assessing and optimizing preclinical Tb-radiopharmaceuticals.

Background: Targeted radionuclide therapy is established as a highly effective strategy for the treatment of metastatic tumors; however, the co-development of suitable imaging companions to therapy remains significant challenge. Theranostic isotopes of terbium (149Tb, 152Tb, 155Tb, 161Tb) have the potential to provide chemically identical radionuclidic pairs, which collectively encompass all modes of nuclear decay relevant to nuclear medicine. Herein, we report the first radiochemistry and preclinical studies involving 155Tb- and 161Tb-labeled crown-alpha MSH, a small peptide-based bioconjugate suitable for targeting melanoma. Methods: 155Tb was produced via proton induced spallation of Ta targets using the isotope separation and acceleration facility at TRIUMF with isotope separation on-line (ISAC/ISOL). The radiolabeling characteristics of crown-alpha MSH with 155Tb and/or 161Tb were evaluated by concentration-dependence radiolabeling studies, and radio-HPLC stability studies. LogD7.4 measurements were obtained for [161Tb]Tb-crown-alpha MSH. Competitive binding assays were undertaken to determine the inhibition constant for [natTb]Tb-crown-alpha MSH in B16-F10 cells. Pre-clinical biodistribution and SPECT/CT imaging studies of 155Tb and 161Tb labeled crown-alpha MSH were undertaken in male C57Bl/6 J mice bearing B16-F10 melanoma tumors to evaluate tumor specific uptake and imaging potential for each radionuclide. Results: Quantitative radiolabeling of crown-alpha MSH with [155Tb]Tb3+ and [161Tb]Tb3+ was demonstrated under mild conditions (RT, 10 min) and low chelator concentrations; achieving high molar activities (23-29 MBq/ nmol). Radio-HPLC studies showed [161Tb]Tb-crown-alpha MSH maintains excellent radiochemical purity in human serum, while gradual metabolic degradation is observed in mouse serum. Competitive binding assays showed the high affinity of [natTb]Tb-crown-alpha MSH toward MC1R. Two different methods for preparation of the [155Tb]Tbcrown-alpha MSH radiotracer were investigated and the impacts on the biodistribution profile in tumor bearing mice is compared. Preclinical in vivo studies of 155Tb- and 161Tb- labeled crown-alpha MSH were performed in parallel, in mice bearing B16-F10 tumors; where the biodistribution results showed similar tumor specific uptake (6.06-7.44 %IA/g at 2 h pi) and very low uptake in nontarget organs. These results were further corroborated through a series of single-photon emission computed tomography (SPECT) studies, with [155Tb]Tb-crown-alpha MSH and [161Tb]Tb-crown-alpha MSH showing comparable uptake profiles and excellent image contrast.