Imaging and therapeutic compositions and methods targeting platelet-derived growth factor receptor.alpha.

Abstract

A peptide construct for targeting PDGFRA includes diagnostic or therapeutic moiety which includes a chelator and a radionuclide. Also disclosed are diagnostic and therapeutic methods using the peptide constructs for diagnosing, imaging or treating cancer, particularly carcinoma of the thyroid, GIST, colon, breast, sarcoma, glioblastoma, or lymphoma.

Description

IMAGING AND THERAPEUTIC COMPOSITIONS AND METHODS TARGETINGPLATELET-DERIVED GROWTH FACTOR RECEPTOR aCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the priority benefit of U.S. Provisional Patent Application No. 63 / 683,167, filed on August 14, 2024, the entire contents of which are incorporated herein by reference, where permitted.FIELD

[0002] The present invention relates to radiopeptides targeting platelet-derived growth factor receptor a (PDGFRA), compositions thereof, and imaging and therapeutic methods related thereto.INTRODUCTION

[0003] The increasing incidence of thyroid carcinoma worldwide, in many cases small volume disease, has sparked broad interest in better monitoring and prognostic tools to avoid overtreatment.1’2While the majority of these cases are ultimately amenableto surgical or radioactive iodine therapy, staging and surveillance remains a challenge given the high propensity for small volume lymphatic and distant spread that can occur many years after the original diagnosis.3’4

[0004] Lymphatic metastases are the most common sites of recurrence, and a significant driver of lymphatic spread and disease recurrence is platelet-derived growth factor receptor a (PDGFRA). PDGFRA overexpression is associated with poor survival in patients with papillary thyroid cancer (PTC) and is a driver of epithelial-to-mesenchymal transition (EMT) creating a cell phenotype with increased cell migration and invasive potential.5’6PDGFRA protein is typically minimally expressed in most normal tissues, but elevated PDGFRA protein expression has been described in human cancers including ovarian, melanoma, gastrointestinal, stromal tumors, glioblastoma, prostate, breast, lung, renal cell and sarcoma.7’8These findings make PDGFRA a promising target for a potential theranostic for the management of carcinoma, especially for those patients at risk of or presenting with metastatic disease.9WSLEGAL\055326\00540\41785915v2 1

[0005] Molecular imaging with radiolabeled probes using positron-emission tomography (PET) is a highly sensitive and non-invasive approach to monitor and characterize PDFGRA and associated disease. Radiopharmaceuticals such as18F-FDG (Vogel, J.; Sekler, J.; Giickel, B.; Pfannenberg, C.; Nikolaou, K.; La Fougere, C.; Dittmann, H.; Reinert, C.P. How [18F]FDG- PET / CT Affects the Management of Patients with Differentiated Thyroid Carcinoma in Clinical Routines. Cancers 2024, 16, 588; Treglia, G.; Sadeghi, R.; Del Sole, A.) and "mTc-MIBI (Schenke SA (2022) Diagnostics 12(6), 1358.) have been described for the use in molecular imaging of papillary thyroid cancer. Limitations of18F-FDG in PTC are low sensitivity due to the slow growingnature of PTC and potentially less glycolytic activity as well as lack of specificity due to uptake in inflammatory disease (Giovanella, L. Diagnostic Performance of PET / CT with Tracers Other than F-18-FDG in Oncology: An Evidence-Based Review. Clin. Transl. Oncol. 2014, 16, 770-775.).99mTc-MIBI has a high negative predictive value (NPV) but suffers from low specificity and positive predictive value (PPV). Those limitations in PTC can be addressed by the development of a68Ga-labeled PDGFRA-targeting peptide as an imaging probe with improved image quality and diagnostic accuracy.

[0006] A64Cu-radiolabeled antibody that targets PDGFRA in PTC in a mouse xenograft model has been described.10However, while demonstrating selectivity, the disadvantages of antibodies include high molecular weight, prolonged clearance times, and immunogenicity.11’12Conversely, peptide-radioisotope conjugates represent favorable alternatives due to easier synthesis, higher tissue penetration, faster clearance from blood, and lower immunogenic potential.13’14Cyclic peptides are an emerging trend in drug discovery and design of radiopharmaceuticals and radiotheranostics to improve metabolic stability and binding affinity. To date, only PDGFRB subtype targeting peptides have been reported in the literature.15'18Askoxylakis et al. identified PDGFR-P1 peptide, a radiolabeled1251 / 1 11 conjugate that displayed promising in vitro PDGFRB targeting but lacking metabolic stability and in vivo binding enhancement.17Effendi et al. used the same peptide to create a67Ga-radiopeptide evaluating different linkers to improve metabolic stability and binding affinity.18These67Ga-peptides with an ethylene glycol linker exhibited high in vivo metabolic stability, but without sufficient tumor accumulation possibly due to the fact that the beta subunit ofPDGFR exhibits relatively high levels of expression in many normal tissues. Unlike PDGFRB, few studies have successfully defined a PDGFRA ligand or drug binding pocket structures and directed efforts to target PDGFRA have been limited.19WSLEGAL\055326\00540\41785915v2 2SUMMARY

[0007] Described herein are novel PDGFRA-targeting peptides and their in vitro and in vivo binding characteristics. Also described is radiolabeling of these peptides with a radioisotope, for example68Ga (t’ =68min), in vivo metabolic stability and in vivo characterization with PET imaging in thyroid cancer mouse models. It is believed that targeting the alpha subunit of PDGFR not only has use in treating thyroid carcinoma, but other carcinomas as well including GIST, colon, breast, sarcoma, glioblastoma, and lymphomas where the efficacy of tyrosine kinase inhibition of PDGFRA signaling has been demonstrated.

[0008] In one aspect, described herein are radiolabeled peptides for use as radiotracers and therapeutic agents, particularly cyclic peptides, for molecular imaging of PDGFR in thyroid cancer and inhibition of PDGFR.

[0009] In one specific example,68Ga-NOTA-CP18.5 has been identified with favorable tumor targeting and pharmacokinetic profile from in vitro and in vivo evaluation of a series of peptides derived from phage display libraries using both phenotypic screening and direct binding methods. CP 18.5 was able to significantly influence the behaviour of immortal cell lines expressing PDGFRA, while also demonstrating direct interactions to PDGFRA in heterodimers with other tyrosine kinase receptors, and PDGFRA homodimers.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1. Scheme for the biopanning strategy of phage library MBX-SXC6C against BCPAP and BONI cells grouped according to cell line and panning method.

[0011] Figure 2 shows the strategy for sequence selection. If sequences were common between Groups 1-4 and Group 5 and those common sequences were also top 26 in relevance within their groups, then peptides were synthesized, cyclized and tested. The complex strategy, using multiple cell lines and cross-referenced with recombinant protein, was designed to provide multiple and overlapping epitopes for presentation.25’26Given the differences in surface binding and cell-based binding can influence binding, we chose multiple formats with the goal to provide a wide selection of potential peptides to target the alpha subunit of PDGFR.

[0012] Figure 3. Screening of cyclic CP 16 and cyclic CP 18 for effects on PDGF-AA-induced migration on BCPAP(+) cells.WSLEGAL\055326\00540\41785915v2 3

[0013] Figure 4. Screening of selected peptide sequences (CP6, CP 16, CP 17, CP 18, CP24, CP25) in the absence and presence of 50 nM PDGF-AA from the biopanning experiment for effects on the phosphorylation of PDGFRA. Data are shown from protein analysis from western blot gels at longer (top) and shorter (below) exposure times. Quantified data from a single gel for the expression of phosphorylated PDGFRA normalized to y-tubulin is shown between the gel blots.

[0014] Figure 5. A) Protein analysis of the effect of single amino acid substitutions on the phosphorylation of PDGFRA in comparison to effects on the phosphorylation on PDGFR0 as well as STAT-3, AKT and Erkl / 2. Quantified data from a single gel for the expression of phosphorylated PDGFRA normalized to y-tubulin is shown between the gel blots.B) Concentration-dependent effects of increasing amounts of cyclic CP18.5 and cyclic CP16.2 peptides on BCPAP(+) cell migration. Data are shown as mean ± SEM from n=3 experiments.

[0015] Figure 6. Original Matrigel 3D growth BCPAP -Alanine scans in CP16 and CP18, including different variants from Alanine substitution (CP16.1, CP16.2, CP16.3, CP16.4 & CP18.5, CP18.6, CP18.7, CP18.8) in comparison to PDGF-AA peptide and empty controls.

[0016] Figure 7. Microscale thermophoresis (MST). Titration concentration-response curves of increasing concentrations of tested target peptides against His-tag-PDGFRA protein in comparison to PDGF-AA and PDGFR0 peptides. The x- and y-axes of each graph show the change (A) Fnorm (° / oo) versus increasing ligand concentrations. Determined KD values are given in the graphs. Data are shown as mean ± SEM from n=3 experiments.

[0017] Figure 8. Visual Interference Color Assay for the analysis of binding of cyclic CP16, CP 16.2, CP 18 and CP 18.5 binding to PDGFRA via color distance (AC). Controls were protein PDGFRA only and peptide only. Data are shown as mean ± SEM from n=3 experiments.

[0018] Figure 9. Flow cytometry of FITC-CP18.5 in BCPAP(-) (left) and BCPAP(+) cells (right). Top line shows the initial signal for FITC-CP18.5 in both cell lines. Next three lines show the effect of pre-treatment with 2 mM cyclic CP18.5, 5 mM PDGFR-P1 peptide, or 100 pg PDGFRA monoclonal antibody on the FITC-CP18.5 signal. The x- and y-axes of each graph show the fluorescence intensity and the number of cells, respectively. The table below presents the ratios of the basis FITC-CP18.5 signal versus pre-treated cells calculated based on the mean fluorescence intensity. Data are shown as mean ± SEM from n=3 experiments.

[0019] Figure 10. In vitro cell uptake of68Ga-labeled PDGFRA-targeting peptides CP 16, CP 18 and CP18.5 into 8305C and BCPAP(-) thyroid cancer cell lines after 15 min (left) and 30 minWSLEGAL\055326\00540\41785915v2 4(right) incubation time. Data are presented as % radioactivity uptake per mg protein and as mean ± SEM from 3-6 data points from n=12 experiments.

[0020] Figure 11. In vivo PET images from dynamic experiments after injection of68Ga-labeled PDGFRA- peptides CP16, CP16.2, CP18 and CP18.5 into 8305C thyroid tumor-bearing NSG mice. Depicted images are shown as maximum intensity projections (MIP) and at 20 min post injection time. Below are the corresponding time-activity curves (TACs) for radioactivity uptake levels into the 8305C tumor tissue (left) and the contralateral non-targeting muscle tissue (right). Data are shown as standardized uptake values (SUV) over the time course of 60 min as mean ± SEM values from n=2-3 mice.

[0021] Figure 12. In vivo PET images data from dynamic experiments after injection of68Ga- labeled PDGFRA-peptide CP-18.5 into BCPAP(+) thyroid tumor-bearing NSG mice. Depicted images are shown as maximum intensity projections (MIP) and at 60 min post injection time from control mouse (left) and mouse co-injected with 300 pg cyclic CP18.5 (right). Below are the corresponding time activity curves (TACs) for radioactivity uptake levels into the BCPAP(+) tumor tissue (left) and the clearance through the kidneys (right). Data are shown as standardized uptake values (SUV) over the time course of 60 min as mean ± SEM values from n=3 mice.

[0022] Figure 13. In vivo metabolic stability of68Ga-labeled CP18 and CP18.5 over 60 min post injection in control BALB / c mice. Data was collected from 2-3 mice and it is displayed as percentage of intact68Ga-labeled peptide and as mean ± SEM for every time point.

[0023] Figure 1468Ga-Labeling of cyclic PDGFRA-targeting peptide NOTA-CP18.5.DESCRIPTION OF EXAMPLES OF EMBODIMENTS

[0024] Before the present invention is described further, it is to be understood that this invention is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0025] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein canWSLEGAL\055326\00540\41785915v2 5be used in the practice or testing of the present invention, the preferred methods and materials are now described.

[0026] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to an amino acid sequence comprising a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residues is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0027] The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids, and isomers thereof. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, carboxyglutamate, O-phosphoserine, and isomers thereof. The term “amino acid analogs” refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. The term “amino acid mimetics” refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid Amino acids can be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0028] The term “artificial amino acid” as used herein refers to an amino acid that is different from the twenty naturally occurring amino acids (alanine, arginine, glycine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, serine, threonine, histidine, lysine, methionine, proline, valine, isoleucine, leucine, tyrosine, tryptophan, phenylalanine) in its side chain functionality. The artificial amino acid can be a close analog of one of the twenty natural amino acids, or it can introduce a completely new functionality and chemistry, as long as the hydrophobicity of the artificial amino acid is either equivalent to or greater than that of the natural amino acid. The artificial amino acid can either replace an existing amino acid in a protein (substitution), or be an addition to the wild type sequence (insertion). The incorporation of artificialWSLEGAL\055326\00540\41785915v2 6amino acids can be accomplished by known chemical methods including solidphase peptide synthesis or native chemical ligation, or by biological methods.

[0029] The following description is provided in order to demonstrate and further illustrate certain embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.

[0030] Different peptide groups were identified based on biopanning experiments with and without the alpha subunit of PDGFR leading to identification of ~50 peptide candidates. Preferred peptides comprise two core peptide sequences (CP 16 and CP 18) that demonstrated significant changes in PDGFRA phosphorylation and cell migration. Alanine scan sub-libraries were created from these two lead peptide sequences and radiolabeled using68Ga-GaC13 at pH 4.5 resulting in RCP>95% within 34-40 min including SPE purification. Cyclic peptide CP18.5 showed strongest effect on cell migration, flow cytometry, and visual interference color binding assay.68Ga-labeled PDGFR-targeting peptides showed elevated cell and tumor uptake in models of thyroid cancer with68Ga-NOTA-CP18.5 being the lead candidate.

[0031] Phage display technology with two separate libraries and seven different cell lines was used through three rounds of biopanning, as well as flow cytometry and comparative analysis with recombinant protein for selecting specific peptide sequences. Phenotypic binding analysis was completed using phosphorylation and cell migration assays. In vitro protein binding was analyzed with thermophoresis and flow cytometry using fluorescent-labeled PDGFR.

[0032] Peptide candidates were modified with NOTA chelator for radiolabeling with68Ga. In vitro cell uptake was studied in various thyroid cancer cell lines. In vivo studies of68Ga-labeled peptides included metabolic stability and small-animal PET imaging.

[0033] Generally, peptides described herein may be linear or cyclic, or be derivatized with a chelating agent such as NOTA (l,4,7-triazacyclononane-l,4,7-triacetic acid) or DOTA (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid), which can serve to carry an imaging or therapeutic radioisotope. In one embodiment, the peptides may comprise the sequence X1-X2-C- X3-X4-X5-X6-X7-X8-C-X9 [SEQ ID No. 1], where:• XI is any amino acid residue such as S;• X2 is either F or N;• X3, X4, X5 are the same or different and are a natural or non-natural hydrophobic amino acid residue, such as Q, F, P, A, V, I , L or cyclobutyl-alanine;WSLEGAL\055326\00540\41785915v2 7• X6 is a natural or non-natural aromatic amino acid residue, such as W, F, Y, or Naphtyl- alanine• X7 and X8 is any amino acid residue, provided at least one of X7 or X8 is R or N; and• X9 is any amino acid residue, such as G.

[0034] In preferred embodiments, the peptides have the sequence SFCPQVWGNCG [SEQ ID No. 2] referred to herein as Pl 6, SNCPQQWRYCG [SEQ ID No. 3] referred to herein as Pl 8, or SNCAQQWRYCG [SEQ ID No. 4] referred to herein as Pl 8.5. When in cyclical form, these peptides are referred to as CP 16, CP 18, and CP 18.5 respectively.

[0035] In some embodiments, the peptides described herein may comprise variants containing conservative amino acid substitutions at various positions, D-amino acid substitutions, or additional peptide dimer or trimer forms for multivalent binding. For example, in some embodiments, the Ala residue could be N-methylated or exchanged for a D-amino acid, or dimerization / multimerization. As used herein, a "conservative amino acid substitution" is a replacement where one amino acid is substituted with an amino acid having similar biochemical properties, for example, charge, hydrophobicity and / or size. In some embodiments, a conservative substitution is an exchange between two amino acids separated by a small physicochemical difference. Generally, conservative amino acid substitutions occur within the same class of amino acids, such as aliphatic, hydroxyl / S containing, cyclic, aromatic, basic and acidic classes.Peptide Constructs with Diagnostic Function

[0036] The disclosed peptides can be conjugated with a functional moiety which is diagnostic and, in some embodiments, comprises a radionuclide reporter appropriate for scintigraphy, SPECT, or PET imaging. The functional moiety may comprise a chelator for this purpose. Constructs in which the PDGFRA imaging agents are conjugated with a chelator for a radionuclide useful for both diagnostic imaging and for radiotherapy are specifically contemplated.

[0037] The chelators can include acyclic chelators (i.e. h2DEDPA; l,2-bis[[(6- carboxypyridin-2-yl)methyl]amino]ethanePSMA), macrocyclic chelators (i.e. NOTA, DOTA; l,4,7,10-Tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid), macrocyclic chelators based on 1,4,7-Triazacyclononane (TACN), and hybrid structure chelators (i.e. DATA; 6-amino-l,4- diazapine-triacetate). The chelator moiety can then be used to carry a radionuclide.

[0038] In some embodiments, the peptide is linked to or comprises a detectable diagnostic moiety which can include biotin, copper-DOTA, biotin-PEG3, aminooxyacetate,19FB,18FB, andWSLEGAL\055326\00540\41785915v2 8FITC-PEG3. In some forms, the diagnostic moiety could comprise of64Cu DOTA,68Ga DOTA,68Ga NOTA,18F, A118F NOTA,64Cu,68Ga,89Zr,1241,86Y,94mTc,nC and76Br.

[0039] In some embodiments, the the diagnostic moiety is an imaging moiety. The term “imaging moiety” refers to a moiety that has been labeled for detection. In some examples, an imaging moiety is isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes such as2H,3H,nC,13C,14C,13N,15N,15O,17O,180,31P,32P,35S,18F,36C1,123I,125I,44SC,64CU,67Ga,These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically-labelled disclosed imaging agents, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled imaging agents can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0040] Also disclosed are radioactively labeled PET, SPECT, or scintigraphic imaging agents that have a suitable level of radioactivity. Generally, the unit dose to be administered has a radioactivity of about 0.01 mCi to about 100 mCi, preferably 1 mCi to 20 mCi. The solution to be injected at unit dosage is from about 0.01 mL to about 10 mL. It is generally preferred to form radioactive complexes in solutions containing radioactivity at concentrations of from about 0.01 mCi to 100 mCi per mL.

[0041] Typical doses of a radionuclide-labeled imaging agent can provide 10-20 mCi. After injection of the radionuclide-labeled imaging agents into the patient, a gamma cameraWSLEGAL\055326\00540\41785915v2 9calibrated for the gamma ray energy of the nuclide incorporated in the imaging agent is used to image areas of uptake of the agent and quantify the amount of radioactivity present in the site. Imaging of the site in vivo can take place in a matter of a few minutes. However, imaging can take place, if desired, in hours or even longer, after the radiolabeled peptide is injected into a patient. In most instances, a sufficient amount of the administered dose will accumulate in the area to be imaged within about 0.1 of an hour to permit the taking of scintiphotos.Peptide Construct Treatment Compositions and Methods

[0042] In some embodiments, the peptide is linked to a functional moiety which is a therapeutic moiety. In some examples, the therapeutic moiety comprises a chelator and a radiotherapeutic radionuclide, such as radionuclide-DOTA and radionuclide-NOTA. Preferably, the therapeutic moiety is177Lu -DOTA,177Lu -NOTA,225Ac-DOTA or225Ac-NOTA.

[0043] In some embodiments, a therapeutic peptide construct may be used in combination with another cancer treatment, such as a tyrosine kinase inhibitor, either sequentially or simultaneously. A peptide construct as described herein may be used as a first treatment, or may be used after the other cancer treatment. Combination therapy to treat cancers is well known in the art.

[0044] A “pharmaceutical composition” refers to a formulation of a compound as disclosed and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.

[0045] The term “condition” as used herein refers generally to a disease, event, or a change in health status. A change in health status may be associated with a particular disease or event, in which case the change may occur simultaneously with or in advance of the disease or event. In those cases where the change in health status occurs in advance of a disease or event, the change in health status may serve as a predictor of the disease or event. For example, a change in health status may be an alteration in the expression level of a particular gene associated with a disease or event. Alternatively, a change in health status may not be associated with a particular disease or event.

[0046] The terms “treat,” “treating,” or “treatment” as used herein generally refer to preventing a condition or event, slowing the onset or rate of development of a condition or delayingWSLEGAL\055326\00540\41785915v2 10the occurrence of an event, reducing the risk of developing a condition or experiencing an event, preventing or delaying the development of symptoms associated with a condition or event, reducing or ending symptoms associated with a condition or event, generating a complete or partial regression of a condition, lessening the severity of a condition or event, or some combination thereof.

[0047] For the purposes of administration, the disclosed peptides may be administered as a raw chemical or may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the disclosed subject matter can comprise a peptide as disclosed herein and a pharmaceutically acceptable carrier, diluent or excipient. The peptide is present in the composition in an amount which is effective to treat a particular disease or condition of interest — that is, and preferably with acceptable toxicity to the patient. Activity of compounds of the peptides can be determined by one skilled in the art, for example, as described in the Examples. Appropriate concentrations and dosages can be readily determined by one skilled in the art.

[0048] Administration of the disclosed compounds, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for serving similar utilities. The disclosed pharmaceutical compositions can be prepared by combining a compound as disclosed with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, intratumoral, or infusion techniques. The disclosed pharmaceutical compositions can be formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units. Actual methods of preparing dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, current edition (Philadelphia College of Pharmacy and Science). The composition to be administered will, in any event, contain a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the description herein.WSLEGAL\055326\00540\41785915v2 11

[0049] A pharmaceutical composition as disclosed may be in the form of a solid or liquid. In one aspect, the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.

[0050] The pharmaceutical composition may be in the form of a liquid, for example, a solution, emulsion or suspension. The liquid may be for delivery by injection. When intended for injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.

[0051] The disclosed liquid pharmaceutical compositions, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

[0052] A disclosed liquid pharmaceutical composition intended for parenteral administration should contain an amount of a disclosed compound such that a suitable dosage will be obtained.

[0053] The pharmaceutical compositions may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.

[0054] The disclosed compounds, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability andWSLEGAL\055326\00540\41785915v2 12length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.

[0055] The disclosed compounds, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents. Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound and one or more additional active agents, as well as administration of the compound and each active agent in its own separate pharmaceutical dosage formulation. For example, a compound and the other active agent can be administered to the patient together in a single dosage composition or each agent administered in separate dosage formulations. Where separate dosage formulations are used, the compounds and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.

[0056] It will also be appreciated by those skilled in the art that in the process described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t- butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-RZZ(where Rzzis alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.

[0057] It will also be appreciated by those skilled in the art, although such protected derivatives of compounds may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form the intended compoundsWSLEGAL\055326\00540\41785915v2 13which are pharmacologically active. Such derivatives may therefore be described as “prodrugs.” All prodrugs of the disclosed compounds are specifically contemplated.

[0058] Furthermore, all of the disclosed compounds that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds can be converted to their free base or acid form by standard techniques.Biopanning and peptide selection

[0059] A general biopanning strategy is outlined in Figure 1. In short, phage-display library Cy5- MBX-SXC6C, expressing 1013different cyclic peptide sequences, were panned for PDGFRA specific binding against two pairs of cell lines (BCPAP and BONI) genetically modified to express the receptor or empty vector. Each group of cell lines underwent three rounds of panning and after deep sequence (Illumina platform and MatLab software analysis)24sequences specific for PDGFRA binding for each group were selected. Sequences were grouped according to the cell line they were selected from; ‘Group 1’ corresponded to BCPAP hits, and ‘Group 2’ to sequences from panning BONI cells. The phage library MBX-SXC6C was panned for binding to recombinant PDGFRa-His protein, the bound phage were eluted and amplified to create a subset library (106clones). This subset-phage-display library was used for a second set of panning with BCPAP and BONI sets of cell lines. After three rounds of panning with the subset library, two new groups of sequences were generated, ‘Group 3’ for BCPAP and ‘Group 4’ for BONI hits. The phage bound to PDGFRa beads vs control beads was also sequenced to generate ‘Group 5’ of sequences.Phenotypic Screening

[0060] The 26 peptide sequences were selected (Figure 2) and their effect on PDGFRa phosphorylation investigated as outlined for a selection in Figure 6. The greatest effects were from CP 16 (77% reduction) and CP 18 (74% reduction). Cell migration was also assessed to reveal that changes in phosphorylation were also reflected in altered migration for CP 16 and CP 18 (Figure 3).

[0061] Both peptides exhibited the -PQXW- sequence motif. A new subset of peptide sequences was derived by way of single amino substitutions (alanine) within this motif that were tested for changes in PDGFRa phosphorylation and cell migration (Figure 5a).WSLEGAL\055326\00540\41785915v2 14

[0062] From these screening experiments 4 peptide sequences were identified as the strongest candidates to continue studying on in vitro and in vivo experiments (cyclic CP 18, cyclic CP18.5, cyclic CP16, cyclic CP16.2); these peptides were also found to be antagonists of PDGF- AA- induced phosphorylation (Figure 5a), subsequent migration (Figure 5b) and growth in Matrigel (Figure 6). The phenotypic approach to screening allowed us to identify the first peptides to target PDGFRA and downstream signaling with an opportunity to modulate PDGFRA function.Preparation and Derivatization of Peptides

[0063] The disclosed peptides can be prepared by procedures known to those of skill in the art. For example, the peptides can be prepared using standard solid-phase peptide synthesis techniques, and modifications thereof. Modified amino acids may be employed to incorporate amino acids comprising alkyne and / or azide moieties and / or alkene moieties useful for cyclization. Methods for cyclizing the peptides using azide / alkyne chemistry and Grubbs metathesis chemistry are well-known in the art. Such methods are described in more detail in the examples.

[0064] Linear peptides can cyclized with a cyclization reaction, such as with a xylene- based linchpin or other suitable linchpin (Timmerman et al. 200521). In one example, the linchpin a,a-dibromo-m-xylene may be used.

[0065] The peptides may be conjugated to an imaging moiety, a reporter moiety, a therapeutic moiety, or a chelator moiety using conventional reactions known in the art. For example, a chelator such as NOTA may be added by reaction with 2-S-(4- Isothiocyanatobenzyl)-l,4,7-triazacyclononane-l,4,7-triacetic acid (pSCN-Bn-NOTA).

[0066] It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below, other peptides not specifically illustrated in the examples below by using the appropriate starting components and modifying the parameters of the synthesis as needed. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein.WSLEGAL\055326\00540\41785915v2 15Peptide synthesis

[0067] PDGFRA-targeting peptides were synthesized in multiple steps from the linear peptide substrate. An automated peptide synthesizer was utilized to generate the linear versions of peptides CP18.5, CP18, CP16 and CP16.2 with the Fmoc / / Bu solid phase strategy. After cleavage from the solid support, HPLC- purification and lyophilization, 19-23.8 mg of the linear peptides were obtained in good yields of 37-50%. A small linchpin in the form of a,a’-dibromo-m-xylene was inserted to access the cyclized peptides according to Timmerman et al.lin a fast and clean reaction. Here, the free thiol groups of the Cys residues in the peptide were reacted with the bromo residues of the linchpin with conversion yields of 95-97% for the cyclized CP18.5, CP16 and CP 16.2 and 84% for cyclized CP 18 after 15-20 min at r.t. that correlate with reported yields.21Isolated yieldswere in the range of 60-81%. Cyclized PDGFRA-targeting peptides were further modified with bifunctional macrocyclic chelator NOTA-Bn-NCS to obtain precursor peptides with a thiourea linkage between the peptide and chelator for radiolabeling with68Ga. In the case of CP18.5, a fluorescent-labeled cyclic CP18.5 (FITC-CP18.5) was synthesized for in vitro flow cytometry studies. While NOTA-modified PDGFRA-targeting peptides were obtained in moderate yields of 47-55%, FITC-CP18.5 yielded 70%. Table 1 gives an overview of all synthesized peptides, including names, sequences, mass and isolated yields.Table 1. Name, sequence, molecular weight (MW), yielded mass and isolated yield of PDGFRA- targeting peptides.WSLEGAL\055326\00540\41785915v2 16Microscale Thermophoresis

[0068] The PDGFRA peptide library, with and without NOTA functional groups and as linear and cyclic peptides (Table 1), was assessed first for direct binding using microscale thermophoresis. This immobilization-free technique follows the directional movement of biomolecules along a temperature gradient established by an IR laser.27Figure 7 displays the doseresponse curves, where the thermophoresis signal is plotted against ligand concentration. Binding affinity was deducted from the dose-response curves and expressed as dissociation constant (KD values). PDGF-AA protein was used as positive control and revealed high binding affinity with a KD of 9 nM. Peptide Ava-BBN2 was selected as negative control as a stable bombesin peptide analog that binds to G-protein coupled receptor GRPR (gastrin-releasing peptide receptor) with high affinity but not to tyrosine-kinase receptor proteins. Peptides of the cyclic CP 18 series exhibited higher binding affinity than peptides of the cyclic CP 16 series. The NOTA-modified cyclic peptides, which were generated for radiolabeling, demonstrated a different trend following NOTA-CP18 > NOTA-CP16 > NOTA-CP18.5 - NOTA-CP16.2 (Fig.7).WSLEGAL\055326\00540\41785915v2 17

[0069] In one embodiment, NOTA-CP18.5 is the lead peptide with a KD of 18 pM showing high binding affinity to PDGFRA. Comparably, the ICso value for PDGFRB -targeting125I- PDGFR-P1 was also in the pM range based on a different assay (radiometric competitive binding assay) in human pancreatic carcinoma BxPC3.17Alongside the PDGFRA-targeting peptide library, we also investigated PDGFRB-targeting non- radioactive peptide PDGFR-P1.17The peptide showed very low binding to PDGFRA with a Kd of 552 pM, potentially attributable primarily as non-specific binding.Visual Interference Color Assay

[0070] A visual interference color assay (VICA™)23was used to assess the ability of the core and alanine-scan variant peptide sequences (cyclic CP16, CP16.2, CP18.0 and CP18.5) to bind soluble, recombinant PDGFRA. Briefly, macromolecular complexes of varying size will shift the observed colours as a function of the affinity of binding for the different compounds.23Shown in Figure 8 are the resulting interference colors after binding of the PDGFRA to different peptides on the surface, in a qualitatively and quantitatively similar sequence to that seen by the microscale thermopheresis.

[0071] We demonstrated that the relative binding of matched levels of cyclic peptides to PDGFRA is maximum with the cyclic CP18.5 peptide variant. Nonsense peptides added to PDGFRA (data not shown), or PDGFRA alone, induced only small changes in the interference color pattern compared to the presence of the cyclic peptides immobilized on the aluminum oxide surface. Overall, this data facilitated the process of identification of PDGFRA-binding peptides and the results were qualitatively consistent among the phenotypic and the molecular studies. The ability to use this approach for comparative studies allowed us to demonstrate the important changes in the behavior of the peptides with respect to protein binding as a consequence of changes in charge and size.Flow cytometry

[0072] Flow cytometry was performed to elucidate on the binding of lead peptide CP 18.5 in its fluorescent labeled version to PDGFRA receptors in BCPAP(+) versus BCPAP(-) cells, outlined in Figure 9. FITC-labeled CP18.5 produced a significant shift in BCPAP(+) cells compared to the negative control (PBS) and in BCPAP(-) cells which was indicative of an increasedWSLEGAL\055326\00540\41785915v2 18binding of FITC-CP18.5 in the PDGFRA expressing BCPAP(+) cell line. Pretreatment with a pharmacological concentration of 2 mM cyclic CP 18.5 led to the same shift in both cell lines BCPAP(+) (15.0±3.3; n=3) and BCPAP(-) (15.1±4.0; n=3) compared to the negative control. In contrast, when treating BCPAP(-) and BCPAP(+) cells with 100 pg of PDGFRA binding monoclonal antibody Lartruvo® (Eli Lilly) prior to addition of FITC-CP18.5, significant blocking was observed especially in BCPAP(+) cells. This could be an indicator that cyclic CP18.5 peptide binds indeed to the binding site of the PDGFRA antibody on the receptor site. Lastly, pretreatment with PDGFRP binding peptide PDGFR-P1 also resulted in blocking in BCPAP(+) cells which may contribute also to a possible heterodimeric PDGFRA / B mediated binding of CP18.5 peptide in BCPAP(+) cells. Overall, results from the flow cytometry experiments were indicative of some binding of cyclic FITC-CP18.5 towards PDGFRA with potential heterodimeric binding, with significantly less avidity for the beta subunit of PDGFR.Radiolabeling of cyclic peptides

[0073] Radiolabeling with positron emitter Ga-68(t'A =68min) was achieved by reacting the high activity fraction of68Ga-GaCh from a 50 mCi68Ge / 68Ga-generator with 50 pg of each of the NOTA-functionalized cyclic peptides (NOTA-CP18.5, NOTA-CP18, NOTA-CP16 & NOTA- CP16.2) in 2 M sodium acetate buffer to give a pH of 4.5 (Figure 14).68Ga-labeled peptides were obtained after 21 min at 60°C monitored by Radio-TLC. Purification with solid phase extraction (SPE) and reformulation in 20% EtOH / saline delivered "Ga-NOTA-peptides in high radiochemical purity

[0074] >95% determined by Radio-HPLC for subsequent in vitro and in vivo testing. Total synthesis time was 30-40 min for each of the 4 "Ga-peptides. Lipophilicity of68Ga-NOTA-CP18.5 was determined as partition coefficient in w-octanol and PBS (pH 7.4) with logD7.4 = -2.77±0.16 (n = 9 / 3). Figure 14 exemplifies the68Ga-labeling reaction ofNOTA-CP18.5.In vitro cell uptake

[0075] Radiolabeled68Ga-NOTA-CP18.5,68Ga-NOTA-CP18 and68Ga-NOTA-CP16 were tested for their in vitro cell uptake properties in native PDGFRA cell line 8305C versus nonexpressing BCPAP(-) cells. Figure 10 summarizes the cell uptake results for those peptides.68Ga- NOTA- CP 18.5 revealed highest uptake in both 8305C cells at both 15 and 30 minutes versus68Ga-WSLEGAL\055326\00540\41785915v2 19NOTA-CP18 and68Ga-NOTA-CP16 (both <1.6% ID / mg), respectively. These novel cyclic peptides show higher uptake in a PDGFRA(+) cell line compared to a PDGFR(-) cell line, similar to that shown for PDGFRA-targeting antibody64Cu-NOTA-D13C6 in a previously published study.10The uptake values for our cyclic peptides are in the same range as67Ga-labeled PDGFRB- targeting PDGFR-P1 peptide analogs (1.29-3.09% ID / mg protein) in BxPC3-luc cells.18As "Ga- NOTA-CP18.5 uptake in 8305C cells was also slightly lower (A 17%) at 30 min compared to 15 min, this was indicative of some levels of a reversible process in binding to the target proteins. Overall,68Ga-NOTA-CP18.5 did perform better in vitro than the other two peptides but some interactions were observed with68Ga-NOTA-CP18.5 to PDGFRB. We note that different cell lines will present unique cell line turnover and cellular internalization of PDGFRA with resulting variations in receptor binding kinetics and peptide retention.22PET Imaging

[0076] 68Ga-labeled PDGFRA-targeting peptides were also evaluated in vivo. For comparison, all four peptides were investigated for their in vivo pharmacokinetics and tumor uptake in the 8305C thyroid cancer xenograft model with native PDGFRA expression using small animal PET. Figure 11 displays representative PET images of all four68Ga-labeled PDFGRA peptides at 20 min p.i. with the corresponding time-activity curves (TACs) in the 8305C tumors and muscle tissues below.68Ga-NOTA-CP18.5 and68Ga-NOTA-CP18 show clear tumor delineation in the left upper flanks of the mice with68Ga-NOTA-CP18.5 being superior to68Ga- NOTA-CP18. Lower tumor uptake is visible with the68Ga-NOTA-CP16 and68Ga-NOTA-CP16.2 peptides. While tumor uptake into a PDGFRA(+)- mouse model has been demonstrated with the PDGFRA- targeting antibody64Cu-NOTA-D13C6 before,10the novel cyclic peptides represent a valid alternative for PDGFRA-targeting. Tumor uptake over time demonstrated rapid radioactivity uptake during the initial phase of 5 min after injection which would correspond to the distribution phase with68Ga-NOTA-CP 18.5>68Ga-NOTA-CP 18>68Ga-NOTA-CP 16=68Ga-NOTA-CP 16.2 followed by a subsequent washout.

[0077] This profile is typical for radiolabeled peptides, including and a fast initial binding phase thatis slowly reversible.28’29At 60 min p.i. considering the equilibration phase68Ga- NOTA-CP18.5 uptake was still 0.31±0.05, while68Ga-NOTA-CP16.2 revealed only the lowest uptake of 0.20±0.02 (60 min p.i.). Muscle uptake and clearance followed a similar profile albeit atWSLEGAL\055326\00540\41785915v2 20an overall lower radioactivity level. Tumor-to-muscle ratios for "Ga-labeled peptides in the 8305C model were calculated: at 10 min p.i. CP16 1.54, CP16.2 1.58, CP18 1.50, CP18.5 1.67 and at 60 min p.i. CP16 2.07, CP16.2 2.5, CP18 1.85, CP18.5 1.94. For a more detailed analysis of CP18.5 in BCPAP(+) tumors, we have determined a tumor-to-muscle ratio of 1.18±0.07 after 10 min p.i. and 2.15±0.29 (both n=3) after 60 min p.i.. Overall, tumor accumulation significantly exceeds healthy tissue as seen in PDGFRB targeting peptides.17Heart uptake due to perfusion was also detected for all 468Ga-PDGFRA-targeting peptides as typical for68Ga-labeled peptides.29For CP16 series both hepatobiliary and renal clearance was noted, however, the CP 18 series demonstrated predominant renal clearance. As demonstrated with67Ga-labeled PDGFR-P1 peptide analogs,18our PDGFRA-targeting peptides revealed fast clearance fast clearance after 60 min in non-targeted tissues but the kidneys.

[0078] While data obtained from PET studies in vivo do not always correlate with 2D in vitro cell uptake studies, the overall biochemical parameters favoring68Ga-NOTA-CP18.5 uptake are consistent with the in vivo uptake profile. We further examined target specificity for “Ga-NOTA- CP18.5 through blocking experiments in the BCPAP(+) xenograft model (Figure 12). For selfblocking pharmacological doses of 300 pg (10 mg / kg) of the cyclic CP18.5 peptide were used. During the early receptor interaction and binding phase, a blocking effect of approximately 40% was detected strongly in support of a direct receptor binding interaction of68Ga-NOTA-CP18.5. However, at this point we cannot distinguish between binding on the dimers or potential PDGFRA / PDFGRB heterodimers. Interestingly, the self-blocking resulted in a strong blocking effect of 50% in the kidneys at 60 min p.i. (SUV6 >mwfrom 6.58±0.63 (control) to 3.22±0.62 (blocking) both n=6 / 3; Figure 12). Interestingly, the observed renal clearance of CP18.5 in the kidneys is consistent with the known expression of PDGFRA in the renal tubular system, one of the few places where the alpha subunit is found in normal tissue.30Also, radioactivity muscle uptake and retention were strongly elevated in the presence of the pharmacological dose of cyclic CP18.5, as well as blood clearance. This effect is in line with the observation of Effendi et al. and their PDGFRB-targeting peptide67Ga-PDGFR-Pl analog.18Metabolic Stability in vivoWSLEGAL\055326\00540\41785915v2 21

[0079] Lastly, the "Ga-labeled peptides of the CP18 series (68Ga-NOTA-CP18.5 and "Ga- NOTA- CP 18) were examined for metabolic stability in vivo (Figure 13). Over the time course of 60 min,

[0080] 68Ga-NOTA-CP18 integrity was consistently higher for each time point compared to68Ga-NOTA-CP18.5 with 60.5%68Ga-NOTA-CP18 vs. 14%68Ga-NOTA-CP18.5 at 60 min p.i.. This was indicative of much lower metabolic stability of68Ga-NOTA-CP18.5 and accounts, in part, for the observed washout profile from the tumor uptake curves. So far, only in vitro metabolic stability has been described for PDGFR (PDGFRB)-targeting peptides, with125L PDGFR-P1 exhibiting a low serum half-life of 4 min,17and67Ga-labeled PDFGR-P1 analogs with 75-80% after 1 h in mouse plasma.18

[0081] Overall, while68Ga-NOTA-CP18.5 reveals a lower metabolic stability in vivo than its68Ga-NOTA-CP18 counterpart, tumor uptake remained higher for68Ga-NOTA-CP18.5 in comparison to68Ga-NOTA-CP18, indicative of a higher affinity for the alpha subunit of PDGFRa. The two peptides differ in only one amino acid in position 4 (Ala for68Ga-NOTA-CP18.5 and Pro for68Ga-NOTA-CP18). Radiometabolites were not identified, but68Ga-NOTA-CP18.5 is more hydrophilic than the parent compound and the difference of one amino acid in CP 18.5 versus CP 18, indicates a metabolite may be a truncated peptide of68Ga-NOTA-CP18.5 cleaved at the Ala position. Similar results were observed with minigastrin peptides by von Guggenberg et al. Proline-substituted minigastrin analogs exhibited a higher metabolic stability in vivo than minigastrin analogs with Alanine with no influence on their tumor uptake.31’32The metabolic stability of68Ga-NOTA-CP18.5 may be addressed to improve its metabolic profile. Beyond the cyclization and the amidated A-terminus of the radiopeptide, in some embodiments, the Ala residue could be A- methylated or exchanged for a D-amino acid, or dimerization / multimerization (Evans BJ, King AT, Katsifis A, Matesic L, Jamie JF. Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals. Molecules. 2020 May 14;25(10):2314., Abbasi Gharibkandi N, Conlon JM, Hosseinimehr SJ. Strategies for improving stability and pharmacokinetic characteristics of radiolabeled peptides for imaging and therapy. Peptides. 2020 Nov; 133 : 170385.), could complement targeting the dimeric PDGFRA receptor through multivalent interaction and improve binding affinity.WSLEGAL\055326\00540\41785915v2 22MATERIAL AND METHODS

[0082] Materials: All chemicals were obtained from MilliporeSigma (ON, Canada). BMX peptides were synthesized via automated solid-phase peptide synthesis (SPPS) using the Syro I peptide synthesizer (Multi Sy nTech / Biotage, Charlotte, NC, U.S.A). A 50 mCi (1850 MBq) iThemba Laboratories68Ge / 68Ga generator from IsoSolutions Inc. (Vancouver, BC, Canada) was used as68Ga source. Mass spectra were recorded on an Agilent Technologies 1260 HPLC with G6130B MSD (LCMS ESI, Santa Clara, CA, U.S.A.) or a Bruker 9.4T Apex-Qe FTICR (Bruker Daltonics, Billerica, MA, USA) for HR-MALDI. Analytical HPLC was performed on a Shimadzu system (Mandel Scientific, Guelph, ON, Canada) equipped with a DGU-20A5 degasser, a SIL- 20A HT autosampler, a LC-20AT pump, a SPD-M20A photo diode array detector, and a Ramona Raytest radiodetector using a Phenomenex Luna lOu C18(2) 100A, 250 x 4.6 mm column. Semipreparative HPLC was performed on a Gilson system (Mandel Scientific, Guelph, ON, Canada) with a 321 pump and a 155 dual wavelength detector installed with a Phenomenex Jupiter lOu Proteo 90A, 250 x 10 mm, 4.5 pm C18 column. UV absorbance was monitored at wavelengths of 210 and 254 nm. Mobile phase consisted of water / 0.2%TFA as solvent A and acetonitrile as solvent B. Human thyroid cancer cell line BCPAP expressing PDGFRA (BCPAP(+)) per transfection or not (BCPAP(-)) from mock transfection as well as human thyroid anaplastic carcinoma cell line 8305C (American Type Tissue Culture Centre, Manassas, VA, U.S.A) were cultivated in High Glucose Dulbecco’s Modified Eagle Medium (DMEM) supplemented with Ham’s F-12 and 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin / streptomycin from Invitrogen (Life Technologies Inc., Grand Island, NY, U.S.A). All animal studies were carried out according to the guidelines of the Canadian Council on Animal Care (CCAC) and approved by the Cross Cancer Institute Animal-Care Committee. In vivo studies were done using control BALB / c and male BCPAP(+) and BCPAP(-) tumor-bearing NSG nude mice (body weight: 20-24 g, Charles River Laboratories, Saint-Constant, QC, Canada). BCPAP(+) tumor-bearing mice also received a doxycycline slow-releasing pellet (0.5 mg / 21 days; Innovative Research of America, Sarasota, FL, USA) that was implanted into the right flank at the same time. For tumor xenografts, about 3 x 106BCPAP(+) or BCPAP(-) or 8305C cells in 200 pL of PBS / Matrigel (50 / 50) were injected subcutaneously into the upper left flank of male nude NSG mice. After 3-5WSLEGAL\055326\00540\41785915v2 23weeks BCPAP(+), BCPAP(-) and 8305C tumors reached sizes of ~500 mm3and were used for the experiments as described.

[0083] Phage Display Libraries: The phage-display library Cy5-MBX-SXC6C, of macrocyclic glycopeptides (10A13 unique cyclic peptide sequences) was generated in one rapid, biocompatible step by reacting phage-displayed libraries of peptides with dichloro-oxime derivatives as previously described.20After incubating the 2xlOA6 cells with 10Al 1 pfu phage library for 1 hr at 4°C, Cy5 cells were sorted and submitted to deep sequence analysis using Illumina platform and MatLab software analysis.23Similarly, phage library MBX-SXC6C was panned for binding to recombinant PDGFRa-His protein, after 90 min incubation at room temperature, the bound phage were eluted and amplified to create a subset library (106clones).

[0084] Peptide Synthesis: All linear PDGFRA-targeting peptides were synthesized by Fmoc-based solid-phase peptide synthesis (SPPS) using a fully automated peptide synthesizer (Syro I, MultiSynTech / Biotage). 50 mg Rink Amide 4-methylbenzhydrylamine (MBHA) resin (100- 200 mesh, loading: 0.78 mmol / g) was used as the solid support. Rink Amide MBHA resin was allowed to swell in 2 mL of dimethylformamide (DMF) for 15 min. Fluorenylmethyloxycarbonyl (Fmoc) group deprotection was achieved by treatment with 40% piperidine / DMF for 5 min, followed by treatment with 20% piperidine / DMF for 15 min. Fmoc- protected amino acids (5 eq.) were activated and coupled using 5 equiv of O-benzotriazole- N,N,N',N'-tetramethyluronium- hexafluoro-phosphate (HBTU), 5 equiv of ethyl-2- cyano-2- (hydroxyimino) acetate (Oxyma), and 10 equiv of N,N-diisopropylethylamine (DIPEA) over a 60 min time period followed by washing steps with DMF. Treatment with an acidic solution containing 87.5% TFA, 5% water, 5% thioanisole, and 2.5% 1,2-ethylenedioxy-diethanedithiol for 3 h 50 min induced cleavage of the assembled peptides from the resin with simultaneous deprotection of amino acid side chains. Resin was removed from the peptide solution through a syringe filter, and peptides were precipitated by the addition of ice-cold diethyl ether. Residual ether was removed by syringe filter, and the precipitated crude peptides were dried under vacuum. HPLC purification using a Phenomenex Jupiter lOuProteo 90A, 250 x 10 mm, 4.5 pm Cl 8 column at a flow rate of 2 mL / min and a gradient of water / 0.2% TFA as solvent A and acetonitrile as solvent B: 0-5 min 20% B, 10 min 35% B, 20 min 50% B, 30-40 min 70% B and subsequent lyophilization gave linear peptides as white solids.WSLEGAL\055326\00540\41785915v2 24linear CP18.5 23.8 mg (18.1 pmol, 47% isolated yield). MW C54H79N19O16S2 1313.54, measured ESI-MS (positive) m / z 1314.3 [M + H]+, 657.8 [M + 2H]2+. HPLC: tR= 14.5 min, purity: 99.8%. linear CP18 19.0 mg (14.2 pmol, 37% isolated yield). MW C56H81N19O16S2 1339.56, measured ESI-MS (positive) m / z 1340.5 [M + H]+, 670.9 [M + 2H]2+. HPLC: tR= 14.3 min, purity: 94.0%. linear CP16. 21.6 mg (18.1 pmol, 48% isolated yield). MW C52H73N15O14S2 1195.49, measured ESI-MS (positive) m / z 1196.3 [M + H]+, 598.8 [M + 2H]2+. HPLC: tR= 16.4 min, purity >85%. linear CP16.2 22.0 mg (19.3 pmol, 50% isolated yield). MW C50H70N14O13S2 1138.47, measured ESI-MS (positive) m / z 1139.3 [M + H]+, 570.3 [M + 2H]2+. HPLC: tR= 16.8 min, purity >92%.PDGFR-P1 (PDGFR / 3 peptide)'. 21.7 mg (13.9 pmol, 36% isolated yield). MW C79H116N18O15 1556.88, measured ESI-MS (positive) m / z 779.2 [M + 2H]2+, 520.2 [M + 3H]3+. HR-MALDI (positive): 1557.89178 [M+H]+. HPLC: tR= 16.2 min, purity: 95.3%.

[0085] Cyclization of linear PDGFRA-targeting peptides: The cyclization reaction was performed according to Timmerman et al. 200521using the linchpin a,a-dibromo-m-xylene. Briefly, a 0.5 mM peptide solution (7.0 mg linear PDGFRA-targeting peptide (1 eq., 5.2-6.1 pmol)) in MeCN / 20 mM NH4HCO3 buffer (pH 7.8) 1 :7 was stirred with 1.6 -2.0 mg (1.05 eq., 5.5-7.5 pmol) a, a- dibromo-m-xylene at room temperature for 20 min to yield 80-96% cyclized PDGFRa-targeting peptide. The reaction mixture was purified with semipreparative HPLC purification using a Phenomenex Jupiter lOu Proteo 90A, 250 x 10 mm, 4.5 pm C18 column at a flow rate of 2 mL / min and a gradient of water / 0.2% TF A as solvent A and acetonitrile as solvent B : 0-10 min 10% B, 25 min 50% B, 30-40 min 80% B, 40-45 min 90% B (tR(cyclic CP18.5)= 27.5 min, tR(cyclic CP18)= 27.7 min, tR(cyclic CP16)= 29.9 min, tR(cyclic CP16.2)= 30.3 min). HPLC solvent was reduced under vacuum using a rotary evaporator. Subsequent lyophilization yielded cyclic PDGFRA-targeting peptides as white powder. Quality control was performed on an analytical Shimadzu HPLC system using a Phenomenex Luna lOu Cl 8(2) 100A, 250 x 4.6 mmWSLEGAL\055326\00540\41785915v2 25column ata constant flow rate of 1 mL / min and the following gradient with water / 0.2% TFA as solvent A and acetonitrile as solvent B: 0-3 min 10% B, 10 min 30% B, 17 min 50% B, 23 min 70% B, 27-30 min 90% B. cyclic CP18.5: 6.1 mg (4.3 pmol, 81% isolated yield). MW C62H85N19O16S2 1415.59, measured ESI-MS (positive) m / z 1416.4 [M + H]+, 708.9 [M + 2H]2+. HR-MALDI (positive): 1416.59223 [M+H]+. HPLC: tR= 15.5 min, purity: 98.2%. cyclic CP 18: 4.3 mg (3.0 pmol, 60% isolated yield). MW C64H87N19O16S21441.60, measured ESI-MS (positive) m / z 1442.4 [M + H]+, 721.9 [M + 2H]2+. HPLC: tR= 15.6 min, purity: 98.4%. cyclic CP16: 4.6 mg (3.5 pmol, 61% isolated yield). MW C60H79N15O14S21297.54, measured ESI-MS (positive) m / z 1298.3 [M + H]+, 649.9 [M + 2H]2+. HR-MALDI (positive): 1298.54409 [M+H]+. HPLC: tR= 17.5 min, purity: 99.0%. cyclic CP16.2: 4.6 mg (3.7 pmol, 60% isolated yield). MW C58H76N14O13S2 1240.52, measured ESI-MS (positive) m / z 1241.3 [M + H]+, 621.4 [M + 2H]2+. HR-MALDI (positive): 1241.52246 [M+H]+. HPLC: tR= 18.1 min, purity: 96.1%.

[0086] Synthesis of optical probe FITC-CP18.5. 2.9 mg (1 eq., 2.0 pmol) cyclic CP18.5 peptidewas incubated with 1.5 mg (1.9 eq., 3.8 pmol) FITC isomer I and 6.9 pL triethylamine (25 eq., 49.7 pmol) in 500 pL DMF at r.t. for 16 h in the dark. The pH was 9.0. HPLC purification of the reaction mixture was performed using a Phenomenex Jupiter lOu Proteo 90A, 250 x 10 mm, 4.5 pm C18 column at a flow rate of 2 mL / min and a gradient of water / 0.2% TFA as solvent A and acetonitrile as solvent B: 0-10 min 10% B, 25 min 50% B, 30-40 min 80% B, 40-45 min 90% B (tR= 30.0 min). HPLC solvent was reduced under vacuum using a rotary evaporator, and lyophilization gave the FITC-modified peptide FITC-CP18.5 as a bright yellow powder (2.5 mg,1.4 pmol, 70% isolated yield). MW C83H96N20O21S3 1804.62, measured ESI-MS (positive) m / z903.4 [M + 2H]2+, 602.9 [M + 3H]3+. HR-MALDI (positive): 1805.62646 [M+H]+. Quality control was performed on an analytical Shimadzu HPLC system using a Phenomenex Luna lOu Cl 8(2) 100A, 250 x 4.6 mm column at a constant flow rate of 1 mL / min and the following gradient with water / 0.2% TFA as solvent A and acetonitrile as solvent B: 0-3 min 10% B, 10 min 30% B, 17 min 50% B, 23 min 70% B, 27-30 min 90% B (tR= 18.0 min, purity: 99.8%).WSLEGAL\055326\00540\41785915v2 26

[0087] Synthesis of Labeling Precursor NOTA-modified PDGFRA-targeting peptide:3 mg (1 eq., 2.1-2.4 pmol) cyclic PDGFRA-targeting peptide (2.5 mg (1 eq., 1.7 pmol for cyclic CP18.5) was dissolved in 75 pL of DMF in a LoBind Eppendorf tube before 1.3-1.8 mg (2.3-3.1 pmol) of 1.3 eq. / ?SCN-Bn-NOTA in 75 pL DMF was added. The pH was adjusted to 9 by the addition of 14- 24 pL (104-176 pmol, 50eq.) triethylamine (TEA). The reaction mixture was incubated at 37 °C for 2 h, then at 25°C overnight before it was subjected to semipreparative HPLC purification. HPLC purification was performed using a Phenomenex Jupiter lOu Proteo 90A, 250 x 10 mm, 4.5 pm C18 column at a flow rate of 2 mL / min and a gradient 10 mM NFLOAcaq (pH 6.6) as solvent A and acetonitrile as solvent B: 0-10 min 10% B, 25 min 50% B, 30-40 min 80% B, 40-45 min 90% B (tR(NOTA-CP18.5) = 27.0 min, tR(NOTA-CP18)= 26.9 min, tR(NOTA- CP16)= 28.8 min, tR(NOTA-CP16.2)= 28.5 min). HPLC solvent was reduced under vacuum using a rotary evaporator, and lyophilization gave the chelator-modified peptide NOTA-peptides as acetate salts (white powder). Quality control was performed on an analytical Shimadzu HPLC system using a Phenomenex Luna lOu C18(2) 100A, 250 x 4.6 mm column at a constant flow rate of 1 mL / min and the following gradient with water / 0.2% TFA as solvent A and acetonitrile as solvent B: 0-3 min 10% B, 10 min 30% B, 17 min 50% B, 23 min 70% B, 27-30 min 90% B.NOTA-CP18.5-. 1.3 mg (0.7 pmol, 47% isolated yield). MW C82H111N23O22S3 1865.74, measured ESI-MS (positive) m / z 934.0 [M + 2H]2+, 623.2 [M + 3H]3+. HR-MALDI (positive): 1866.75107 [M+H]+. HPLC: tR= 16.4 min, purity >95%.NOTA-CP18'. 1.9 mg (1.0 pmol, 49% isolated yield). MW C84H113N23O22S3 1891.76, measured ESI-MS (positive) m / z 946.9 [M + 2H]2+, 631.9 [M + 3H]3+. HR-MALDI (positive): 1892.76759 [M+H]+. HPLC: tR= 16.2 min, purity: 94.0%.NOTA-CP16-. 2.2 mg (1.3 pmol, 55% isolated yield). MW C80H105N19O20S3 1747.69, measured ESI-MS (positive) m / z 874.9 [M + 2H]2+, 583.9 [M + 3H]3+. HR-MALDI (positive): 1748.70203 [M+H]+. HPLC: tR= 18.7 min, purity: 95.0%.WSLEGAL\055326\00540\41785915v2 27NOTA-CP16.2: 2.2 mg (1.3 pmol, 54% isolated yield). MW C78H102N18O19S3 1690.67, measured ESI-MS (positive) m / z 846.7 [M + 2H]2+, 564.8 [M + 3H]3+. HR-MALDI (positive): 1692.66453 [M+H]+. HPLC: tR= 19.2 min, purity: 97.0%.

[0088] Synthesis of Ga-NOTA-modified PDGFRA-targeting peptides: 1.2 mg (1 eq., 0.6 pmol) NOTA-CP18.5 and 2.0 mg (12 eq., 7.8 pmol)natGa(NC>3)3 were dissolved in 220 pL of 10% MeCN / 1 M NaOAc buffer (pH 4.5, trace-metal grade) in a LoBind Eppendorf tube. The pH of the reaction mixture was 4.5. After incubation at 37 °C for 2.5 h, semipreparative HPLC purification was performed using a Phenomenex Jupiter lOu Proteo 90A, 250 x 10 mm, 4.5 pm C18 column at a flow rate of 2 mL / min and a gradient of 10 mM NH4OAcaq(pH 6.6) as solvent A and acetonitrile as solvent B: 0-10 min 10% B, 25 min 50% B, 30-40 min 80% B, 40-45 min 90% B (tR(natGa-NOTA-CP18.5) = 28.2 min). HPLC solvent was reduced under vacuum using a rotary evaporator, and lyophilization gavenatGa-NOTA-CP18.5 peptide as a white powder. Quality control was performed on an analytical Shimadzu HPLC system using a Phenomenex Luna lOu Cl 8(2) 100A, 250 x 4.6 mm column at a constant flow rate of 1 mL / min and the following gradient with water / 0.2% TFA as solvent A and acetonitrile as solvent B: 0-3 min 10% B, 10 min 30% B, 17 min 50% B, 23 min 70% B, 27-30 min 90% B.natGa-NOTA-CP 18.5: 0.5 mg (0.3 pmol, 42% isolated yield). MW C82Hio8GaN23C>22S3 1931.65, measured ESI-MS (positive) m / z 967.3 [M + 2H]2+, 645.5 [M + 3H]3+. HPLC: tR= 15.9 min, purity >99.2%.

[0089] Western Blot and Flow Cytometry for PDGFRA expression in BCPAP and BONI cell lines: Stable gene transfer and expression of PDGFRA in BCPAP cells has been described elsewhere22To express human PDGFRa complementary DNA in Boni cells, we used a doxycycline-inducible retrovirus system (Lenti-X Lentiviral Expression Systems; Clontech Laboratories, Inc., Mountain View, CA, USA). Briefly, cells were first transduced with theLVX- Tet-On advanced lentivirus (Neo +) followed by selection in G418 (1.0 mg / mL). Resistant cells were then transduced with the LVX-Tight-Puro (Puro +) vector or sequence-verified derivatives expressing wild-type human PDGFRa complementary DNA, followed by selection in puromycin (2.5 pg / mL). Complementary DNA expression was induced by addition of doxycycline (2 pg / mL) (Figure 13).WSLEGAL\055326\00540\41785915v2 28

[0090] Visual Interference Color Assay (VICA)23: Typically, 18 pL drops of protein- peptide mixtures, and their corresponding controls, were deposited onto 7 mm diameter circles on the anodized aluminum oxide surface and incubated for 20 minutes at room temperature under 100% relative humidity. The slides were rinsed thoroughly with deionized water and subsequently washed in IxPBS solution for 5 minutes. The aluminum oxide slides were photographed with the use of a polarizing film to eliminate p-polarized light off the device surface and viewed at an incidence angle of 75° to generate the strongest color contrast by matching s-polarized light reflection intensities off the alumina and underlying surfaces. The red, green, and blue (RGB) coordinate system was used to quantitatively define the visible colors. The color difference or distance (AC) was calculated according to the formula: distance2=(R2-Rl)2+(G2-Gl)2+(B2-Bl)2.]

[0091] Flow Cytometry: BCPAP(-) and BCPAP(+) cells were seeded into 6-well plate with the concentration of 100’000 cells per well one night before. Cells were pre-treated with 2 mM cyclic CP18.5, 5 mM PDGFR-P1 peptide, or 100 pg PDGFRA monoclonal antibody (Lartruvo®, Eli-Lilly) The PBS was then aspirated, and cells were washed with 5 ml PBS per well. Cells were then incubated with 20 pM FITC-CP18.5 (1% DMSO / PBS solution) in 200 pL PBS for 30min, with gentle rocking every 5 min. All procedures containing FITC labeled compounds were performed in the dark. PBS was aspirated, and cells were washed again with 5 ml PBS. 200 pL of trypsin was added to each well, and the plates were placed in the sterile 37°C incubator for 2 min. A total of 1 mL of DMEMZF- 12 (Thermo Fisher Scientific) with 10% fetal bovine serum (Thermo Fisher Scientific) and 1% penicillinstreptomycin medium was added to inactivate trypsinization. The cell solution was then transferred into 15-ml centrifuge tubes and was centrifuged at 1,600 rpm for 5 min. The supernatant was aspirated, and the pellet was resuspended in 10 mL PBS and centrifuged again at 1,600 rpm for 5 min. PBS was aspirated, cells were fixed in 5 mL of ethanol / PBS (1 : 1) solution for 1 h, with occasional mixing. After fixation, the tubes were centrifuged at 1,600 rpm for 5 min. The supernatant was aspirated, and the cell pellet was washed with 10 mL PBS. The pellet was resuspended in 1 mL of PBS and was transferred to a labeled FACS tube (352054; Coming), wrapped in foil, and then placed on ice until they were analyzed. Quantification was done using a BD FACSCanto II (BD Biosciences, San Jose, CA, USA) Flow Cytometer using FACSDiva 8.0 Software. Analysis was performed using FlowJo 8.0.A Student’s t-test was performed to determine statistical significance.WSLEGAL\055326\00540\41785915v2 29

[0092] Thermophoresis: 12 pL 6X His-tag-PDGFR protein (1 pg / pL) was diluted in 930 pL phosphate-buffered saline (pH 7.4) with 0.05% Tween-20 (PBS-T). 20 pL of 100 nM of Monolith His-Tag Labeling Kit RED-tris-NTA 2nd Generation (MO-L018) (NanoTemper Technologies) was added to the His-tag-PDGFR dilution and the mixture was incubated on a thermoshaker att600 rpm for 60 minutes at room temperature in dark. The final concentration of the fluorescently labeled 6X His-tag-PDGFR protein was 100 nM. All the compounds were first diluted to the concentration of 6 mM in DMSO, and then to 3 mM with PBS-T to prevent precipitation. Low-binding tips and tubes were used for the entire process of MST. Serial dilutions of each compound were prepared by adding 1 pL stock solution to 9 pL PBS-T (Tube 1, final concentration of 300 pM), and transfer 5 pL of tube 1 solution to tube 2 that already had 5 pL PBS-T inside (Tube 2, final concentration of 150 pM). 5 pL tube 2 solution was then transferred to tube 3 that already had 5 pL PBS-T (Tube 3, final concentration of 75 pM). This process stopped until reaching tube 16 with final concentration of 0.0046 pM. 5 pL of the labeled 6X His- tag-PDGFR protein (lOOnM) was added to each serially diluted tube, then the mixed solutions were loaded into capillaries. MicroScale thermophoresis experiments were performed on a NanoTemper® Monolith NT.115 (NanoTemper Technologies).

[0093] Phosporylation and Transwell Invasion Assays: To document the effect of the cyclic peptides on PDGFRA activation by PDGF-AA, BCPAP cells expressing PDGFRA and controls, were pre- treated with 10 mM to 10 pM of cyclic peptide for 30 min followed by activation with PDGF-AA (50 nM) for 10 or 20 min. Cells were lysed in RIPA buffer (150 mM NaCl, 100 mM Tris (pH 8.0), 1% Triton X- 100, 1% deoxy cholic acid, 0.1% SDS, 5 mM EDTA, and 10 mM NaF) supplemented with 1 mM sodium vanadate, 2 mM leupeptin, 2 mM aprotinin, 1 mM phenylmethyl sulfonyl fluoride (PMSF), 1 mM DTT, 2 mM pepstatin, and 1 : 100 protease inhibitor cocktail set III on ice. After centrifugation at 4°C at 18,000 rpf for 15 min, the supernatant was harvested as the total cellular protein extract, aliquoted and stored at -80°C. Protein concentration was determined using PierceTM BC A Protein Assay Kit (Pierce Biotechnology, Rockford, IL, USA). Aliquots (usually 50 pg) of protein extract samples were resolved by SDS-PAGE and transferred to nitrocellulose membrane, blocked in 5% non-fat milk in TBS containing 0.05% Tween-20 for 60 min, followed by incubation with primary antibodies 4°C overnight (phospho- PDGFRa [EP2478]:(Y720) and (Y742) wereWSLEGAL\055326\00540\41785915v2 30from Abeam Inc. (Waltham, MA, USA); [23B2]: (Y754) and phospho-PDGFRb [88H8]: (Y751) from Cell Signaling Technology (Danvers, MA, USA)). Protein bands were detected by incubation with horseradish peroxidase-conjugated antibodies (Pierce Biotechnology, Rockford, IL, USA) and visualized with SuperSignal West Pico chemiluminescence substrate (Thermo Scientific, Rockford, IL, USA). To assess cell migration after treatment with cyclic peptides, 8 pm polycarbonate membranes were incubated in fibronecting (10 pg / mL in PBS, at 4 °C, overnight). Serum starved cells were seeded at a density of 5xl04cells / well after 20 minutes of cyclic peptide exposure (60-0.1 pM). Migration towards PDGF-AA (100 nM) as chemo attractant was measured after 4 hours by crystal blue staining of the membrane.

[0094] Radiolabeling of PDGFRA-targeting peptides. Ga-labelin of NOTA- CP18.5 (n=32): Radionuclide "Ga was eluted with ~5 mL of 0.6 N HC1 (trace-metal grade) from the68Ge / 68Ga generator via automated GRP module (Scintomics GmbH, Fuerstenfeldbruck, Germany). The high activity fraction of the68Ga-eluate (1.5 mL) was collected in the plastic reaction vessel while the rest of the radioactivity being dispensed in the 20 mL syringe of the GRP module dispenser unit. 50 pg lyophilized NOTA-CP18.5 was reacted with 1000 pL68Ga-GaCh and 500 pL 2 M NaOAc buffer (pH 8.0) at 60°C (21 min, pH 4.5) in a LoBind Eppendorf tube using a Thermoshaker. "Ga-incorporation was monitored by Radio-TLC (silica TLC plates, mobile phase: 0.1 M citric acid, Rf(free68Ga) = 0.9-1.0, Rf (68Ga-NOTA-CP18.5) = 0.0-0.1). The reaction mixture was diluted with 9 mL DI H2O and subjected to solid-phase extraction using a Sep-Pak C18 Plus cartridge (preconditioned with 5 mL MeCN and 10 mL DI H2O).68Ga-NOTA-CP18.5 was eluted with EtOH in fractions of 2 drops. Typically,68Ga-NOTA-CP18.5 was recovered in fractions 4-6. For subsequent in vitro and in vivo evaluation, 50 pL of the68Ga- NOTA-CP18.5 fraction was formulated with 200 pL saline. Quality Control was performed using analytical Radio-HPLC at a constant flow rate of 1 mL / min and the following gradient with water / 0.2% TFA as solvent A and acetonitrile as solvent B: 0-3 min 10% B, 10 min 30% B, 17 min 50% B, 23 min 70% B, 27-30 min 90% B (tR (68Ga-NOTA-CP18.5) = 16.0 min, Radiochemical Purity: 95- 98%). Total synthesis time was 30-40 min. Radiochemical Yield: 16-20% (d.c.) for one injectable68Ga-NOTA-CP18.5 product fraction.WSLEGAL\055326\00540\41785915v2 31

[0095] The followingsGa-labeled PDGFRA-targeting peptides have been synthesized according to the above-mentioned protocol for68Ga-NOTA-CP18.5.68Ga-NOTA-CP18 (n=5): Total synthesis time: 30-49 min. Radiochemical Yield: 11-31% (d.c.) for one injectable68Ga-NOTA-CP18 product fraction. Radiochemical Purity > 95%, tR (HPLC) = 16.2 min.68Ga-NOTA-CP16 (n=3): Total synthesis time: 30-34 min. Radiochemical Yield: 11-16% (d.c.) for one injectable68Ga-NOTA-CP16 product fraction. Radiochemical Purity > 95%, tR (HPLC) = 18.6 min.68Ga-NOTA-CP16.2 (n=l): Total synthesis time: 34 min. Radiochemical Yield: 22% (d.c.) for one injectable68Ga-NOTA-CP16.2 product fraction. Radiochemical Purity > 95%, tR(HPLC) =19.1 min.

[0096] Determination of Lipophilicity of ^Ga-NOTA-CPl 8.5: Lipophilicity was determined according to the shake-flask method by determining the partition coefficient of68Ga-NOTA-CP18.5 in / / -octanol and PBS buffer (pH 7.4) as aqueous phase. The organic and the aqueous phase were pre-saturated 24 h before the actual start of the experiment. 500 pL of each layer were added to 0.9-2 MBq of68Ga-NOTA-CP18.5 in a LoBind Eppendorf tube, and the mixture was mixed vigorously for 3 min. The layers were allowed to separate by centrifugation at 2000 rpm for 5 min. Aliquots of 100 pL were removed from each phase and measured in a Wizard gamma counter (Wallac 1480 Wizard-3, PerkinElmer, Woodbridge, Ontario, Canada). Calculated logD7.4 values are expressed as mean ± SD from 3 experiments each performed in triplicate.

[0097] In vitro Cell Uptake Studies: BCPAP(+), BCPAP(-) and 8305C cells were grown in 12-well plates (100 000 cells / well). BCPAP(+) and BCPAP(-) cells were treated with doxycycline (2pg / mL) at least 48 h before the in vitro experiment. Medium was removed 1 h prior to the experiment, cells were washed 2 times with PBS. Next, 500 pL Krebs-Ringer solution with 0.1-0.5 MBq68Ga-NOTA-CP18.5 (68Ga-NOTA-CP18 or68Ga- NOTA-CP16) was added to each well. Plates were incubated at 37°C for specific time points (5, 15, 30, 60 min). Radiotracer uptake was stopped with 1 mL ice-cold PBS, and cells wereWSLEGAL\055326\00540\41785915v2 32washed 2 times with PBS and lysed in 0.4 mL lysis buffer (50 mM Tris, 150 mM NaCl, 0.1% SDS, 0.5% sodium deoxy cholate, 0.5% Triton X). Radioactivity in cell lysates was measured using Hidex Automatic Gamma Counter (Turku, Finnland via GTL, Mississauga, Ontario, Canada). Total protein concentration in the samples was determined using a Pierce Bicinchoninic Acid-Based Protein Assay (ThermoFisher Scientific). Data were calculated as the percentage of total added radioactivity per milligram of protein.

[0098] Dynamic PET Imaging Studies: PET imaging of PDGFRA-targeting68Ga- NOTA-peptides was performed on an INVEON® PET / CT scanner (Siemens Preclinical Solutions, Knoxville, TN, U.S.A.). Prior to radiotracer injection, mice were anesthetized through inhalation of isoflurane in 40% oxygen / 60% nitrogen (gas flow 1 L / min), and body temperature was kept constant at 37 °C. Mice were placed in a prone position into the center of the field of view. A transmission scan for attenuation correction was not acquired. Mice were injected with 4-8 MBq of "Ga-NOTA- CP18.5 (68Ga-NOTA-CP18 or68Ga-NOTA-CP16 or68Ga-NOTA-CP16.2) in 150 pL of 20% EtOH / saline solution through a tail vein catheter. For blocking studies with peptide68Ga-NOTA- CP18.5 BCPAP(+)-tumor-bearing NSG mice were pre-dosed i.v. with 300 pg of cyclic CP18.5 (15 min prior to radiotracer injection) in 50 uL saline. Data acquisition was performed over 60 min in 3D list mode. The dynamic list mode data were sorted into sinograms with 54-time frames (10 x 2, 8 x 5, 6 x 10, 6 x 20, 8 x 60, 10 x 120, 6 x 300 s). The frames were reconstructed using maximum a posteriori (MAP) as reconstruction mode. No correction for partial volume effects was applied. The image files were processed using the ROVER v2.0.51 software (ABX GmbH, Radeberg, Germany). Masks defining 3D regions of interest (ROI) were set, and the ROIs were defined by thresholding. ROIs covered all visible tumor mass of the subcutaneous tumors, and the thresholds were defined by 50% of the maximum radioactivity uptake level. Mean standardized uptake values [SUVmean = (activity / mL tissue) / (injected activity / body weight), mL / g] were calculated for each ROI, and time-activity curves (TAC) were generated. All semi-quantified PET data are presented as means ± SEM. Statistical differences were tested by Student’s t test and were considered significant for p < 0.05.

[0099] Metabolic Stability in vivo'. For metabolic stability studies in vivo, control BALB / c mice were anesthetized through inhalation of isoflurane in 40% oxygen / 60% nitrogen (gas flow 1 L / min) prior to i.v. radiotracer injection via the tail vein. Mice wereWSLEGAL\055326\00540\41785915v2 33injected with 25-30 MBq of “Ga- NOTA-CP18.5 or68Ga-NOTA-CP18 in 150 pL 20% EtOH / saline. Venous blood samples were collected at 5, 15, 30, and 60 min post injection via the mouse tail vein and further processed.

[0100] Blood cells were separated by centrifugation (13,000 rpm x 5 min). Supernatant was removed, and the contained proteins were precipitated by addition of 2 volume parts of methanol (2 vol of MeOH / 1 vol of sample). Another centrifugation step (13,000 rpm x 5 min) was performed to obtain plasma. The clear plasma supernatant was injected onto a Shimadzu HPLC system. The samples were analyzed using a Phenomenex Luna lOu Cl 8(2) 100A, 250 x 4.6 mm column at a constant flow rate of 1 mL / min, and the following gradient with water / 0.2% TFA as solvent A and acetonitrile as solvent B: 0-3 min 10% B, 10 min 30% B, 17 min 50% B, 23 min 70% B, 27-30 min 90% B.Interpretation

[0101] The description of the present invention has been presented for purposes of illustration and description, but it is not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. Embodiments were chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated. To the extent that the following description is of a specific embodiment or a particular use of the invention, it is intended to be illustrative only, and not limiting of the claimed invention.

[0102] The corresponding structures, materials, acts, and equivalents of all means or steps plus function elements in the claims appended to this specification are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed.

[0103] References in the specification to "one embodiment", "an embodiment", etc., indicate that the embodiment described may include a particular aspect, feature, structure, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the sameWSLEGAL\055326\00540\41785915v2 34embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to combine, affect or connect such aspect, feature, structure, or characteristic with other embodiments, whether or not such connection or combination is explicitly described. In other words, any element or feature may be combined with any other element or feature in different embodiments, unless there is an obvious or inherent incompatibility between the two, or it is specifically excluded.

[0104] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with the recitation of claim elements or use of a "negative" limitation. The terms “preferably,” “preferred,” “prefer,” “optionally,” “may,” and similar terms are used to indicate that an item, condition or step being referred to is an optional (not required) feature of the invention. The singular forms "a," "an," and "the" include the plural reference unless the context clearly dictates otherwise. The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated.

[0105] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. A recited range (e.g., weight percents or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.

[0106] As will also be understood by one skilled in the art, all ranges described herein, and all language such as "up to", "at least", "greater than", "less than", "more than", "or more", and the like, include the number(s) recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above.WSLEGAL\055326\00540\41785915v2 35References

[0107] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The listing of such publications is not to be construed as an admission of any matter. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.1. Pizzato, M.; Li, M.; Vignat, J.; Laversanne, M.; Singh, D.; La Vecchia, C.; Vaccarella, S. The epidemiological landscape of thyroid cancer worldwide: GLOBOCAN estimates for incidence and mortality rates in 2020. Lancet Diabetes Endocrinol. 2022, 10 (4), 264-272.2. Lam, D.; Davies, L.; Sawka, A. M. Women and thyroid cancer incidence: overdiagnosis versus biological risk. Curr. Opin. Endocrinol. Diabetes Obes. 2022, 29 (5), 492-496.3. Gronlund, M. P.; Jensen, J. S.; Hahn, C. H.; Gronhoj, C.; Buchwald, C. V. Risk Factors for Recurrence of Follicular Thyroid Cancer: A Systematic Review. Thyroid 2021, 37( 10), 1523- 1530.4. Wang, L. Y.; Ganly, I. Post-treatment surveillance of thyroid cancer. Eur. J. Surg. Oncol. 2018, 44 (3), 357-366.5. Lopez-Campistrous, A.; Adewuyi, E. E.; Williams, D. C.; McMullen, T. P. W. Gene expression profile of epithelial-mesenchymal transition mediators in papillary thyroid cancer. Endocrine 2021, 72 (2), 452-461.6. Wang, L. Y.; Ganly, I. Nodal metastases in thyroid cancer: prognostic implications and management. Future Oncol. 2016, 12 (7), 981-94.7. Oseini, A.M.; Roberts, L.R. PDGFRa: a new therapeutic target in the treatment of hepatocellular carcinoma? Expert Opinion on Therapeutic Targets 2009; 73:443-454.8. Heldin, C. Targeting the PDGF signaling pathway in tumor treatment. Cell Communication & Signaling 2013, 77, 1-45.9. Zhang, J.; Wang, P.; Dykstra, M.; Gelebart, P.; Williams, D.; Ingham, R.; Adewuyi, E. E.; Lai, R.; Mcmullen, T. Platelet-derived growth factor receptor-a promotes lymphatic metastases in papillary thyroid cancer. The Journal of Pathology 2012, 228, 241-250.10. Wagner, M.; Wuest, M., Hamann, I.; Lopez-Campistrous, A.; McMullen, T. P. W.; Wuest F. Molecular imaging of platelet-derived growth factor receptor alpha (PDGFRa) in papillary thyroid cancer using immuno-PET. Nucl. Med. Biol. 2018, 58, 51-58.11. Colombo, I.; Overchuk, M.; Chen, J.; Reilly, R. M.; Zheng, G.; Lheureux, S.WSLEGAL\055326\00540\41785915v2 36Molecular imaging in drug development: Update and challenges for radiolabeled antibodies and nanotechnology. Methods 2017, 130, 23-35.12. Kramer, C. S.; Dimitrakopoulou-Strauss, A. Immuno-Imaging (PET / SPECT)-Quo Vadis? Molecules 2022, 27 (10), 3354.13. Kr^cisz, P.; Czamecka, K.; Krolicki, L.; Mikiciuk-Olasik, E.; Szymanski, P. Radiolabeled Peptides and Antibodies in Medicine. Bioconjugate Chemistry 2021, 32 (1), 25-42.14. Pandey, S.; Malviya, G.; Chottova Dvorakova, M. Role of Peptides in Diagnostics. International Journal of Molecular Sciences 2021, 22 (16), 8828.15. Shim, A. H.; Liu, H.; Focia, P. J.; Chen, X.; Lin, P.C.; He, X. Structures of a platelet- derived growth factor / propeptide complex and a platelet-derived growth factor / receptor complex. Proc Natl Acad Sci USA 2010, 107 (25), 11307-1216. Kuai, J.; Mosyak, L.; Brooks, J.; Cain, M.; Carven, G.J.; Ogawa, S.; Ishino, T.; Tam, M.; Lavallie, E. R.; Yang, Z.; Ponsel, D.; Rauchenberger, R.; Arch, R.; Pullen, N. Characterization of binding mode of action of a blocking anti -platelet-derived growth factor (PDGF)-B monoclonal antibody, MOR8457, reveals conformational flexibility and avidity needed for PDGF-BB to bind PDGF receptor-P. Biochemistry 2015, 54 (10), 1918-29.17. Askoxylakis, V.; Marr, A.; Altmann, A.; Markert, A.; Mier, W.; Debus, J.; Huber, P. E.; Haberkorn, U. Peptide-based targeting of the platelet-derived growth factor receptor beta. Mol Imaging Biol. 2013, 15 (2), 212-21.18. Effendi, N.; Mishiro, K.; Shiba, K.; Kinuya, S.; Ogawa, K. Development of Radiogallium- Labeled Peptides for Platelet-Derived Growth Factor Receptor P (PDGFRP) Imaging: Influence of Different Linkers. Molecules 2021, 26 (1), 41.19. Teuber, A.; Schulz, T.; Fletcher, B.S.; Gontla, R.; Muhlenberg, T.; Zischinsky, M. L.; Niggenaber, J.; Weisner, J.; Kleinbblting, S. B.; Lategahn, J.; Sievers, S.; Muller, M.P.; Bauer, S.; Rauh, D. Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA. Nat Commun. 2024, 15 (1), 63.20. Ng, S.; Derda, R. Phage-displayed macrocyclic glycopeptide libraries. Org. Biomol. Chem. 2016, 14, 5539-5545.21. Timmerman, P.; Beld, J.; Puijk, W. C.; Meloen, R. H. Rapid and quantitative cyclization of multiple peptide loops onto synthetic scaffolds for structural mimicry of protein surfaces. Chem. Bio. Chem. 2005, 6 (5), 821-4.22. Lopez-Campistrous, A.; Adewuyi, E. E.; Benesch, M. G. K.; Ko, Y. M.; Lai, R.; Thiesen, A.; Dewaid, J.; Wang, P.; Chu, K.; Ghosh, S.; Williams, D. C.; Vos, L. J.; Brindley, D. N.; McMullen, T. P. W. PDGFRot Regulates Follicular Cell Differentiation Driving Treatment Resistance and Disease Recurrence in Papillary Thyroid Cancer. EBioMedicine 2016, 12, 86-97.23. Lopez-Campistrous, A.; Sweet, H.; Terry, C.; Garen, C.; Wan,Y.; Burrell, R. E.; Moxham, K.; Nickel, M.; McMullen, T. P. W. Label-free protein detection and bindingWSLEGAL\055326\00540\41785915v2 37revealed by a rapid, quantitative, two-step, amplifiable visual interference assay. Nat. Communications. (Submitted).24. Matochko, W. L.; Chu, K.; Jin, B.; Lee, S. W .; Whitesides, G. M.; Derda, R. Deep sequencing analysis of phage libraries using Illumina platform. Methods 2012, 58 (1), 47- 55.25. Panagides, N.; Zacchi, L.F.; De Souza, M.J.; Morales, R. A. V.; Karnowski, A.; Liddament, M. T.; Owczarek, C. M.; Mahler, S. M.; Panousis, C.; Jones, M. L.; Fercher, C. Evaluation of Phage Display Biopanning Strategies for the Selection of Anti-Cell Surface Receptor Antibodies Int. J. Mol. Sci. 2022, 23 (15), 8470.26. Schrofelbauer, B.; Kimes, P. K.; Hauke, P.; Reid, C. E.; Shao, K.; Hill, S. J.; Irizarry, R.; Hahn, W. C. Discovery of antibodies and cognate surface targets for ovarian cancer by surface profiling. Proc Natl Acad Sci USA 2023, 120 (1), e2206751120.27. Magnez, R.; Bailly, C.; Thuru, X. Microscale Thermophoresis as a Tool to Study Protein Interactions and Their Implication in Human Diseases. Int. J. Mol. Sci. 2022, 23, 7672.28. Richter, S.; Wuest, M.; Bergman, C. N.; Way, J. D.; Krieger, S.; Rogers, B. E.; Wuest, F. Rerouting the metabolic pathway of (18)F -labeled peptides: the influence of prosthetic groups. Bioconjug Chem. 2015, 26 (2), 201-12.29. Richter, S.; Wuest, M.; Bergman, C. N.; Krieger, S.; Rogers, B. E.; Wuest, F. Metabolically Stabilized (68)Ga-NOTA-Bombesin for PET Imaging of Prostate Cancer and Influence of Protease Inhibitor Phosphoramidon. Mol Pharm. 2016, 13 (4), 1347-57.30. Ostendorf, T.; Boor, P.; van Roeyen, C.R.C.; Floege J. Platelet-derived growth factors (PDGFs) in glomerular and tubulointerstitial fibrosis. Kidney International Supplements 2014, 4 65-69.31. Klingler, M.; Hormann, A. A.; Rangger, C.; Desrues, L.; Castel, H.; Gandolfo, P.; von Guggenberg, E. Stabilization Strategies for Linear Minigastrin Analogues: Further Improvements via the Inclusion of Proline into the Peptide Sequence. J. Med. Chem. 2020, 63 (23), 14668-14679.32. Notni, J.; Pohle, K.; Wester, H. J. Comparative gallium-68labeling of TRAP-, NOTA-, and DOTA-peptides: practical consequences for the future of gallium-68-PET. EJNMMIRes. 2012, 2 (1), 28.WSLEGAL\055326\00540\41785915v2 38

Claims

CLAIMS1. A peptide for targeting PDGFRA, and comprising the amino acid sequence X1-X2-C-X3- X4-X5-X6-X7-X8-C-X9 [SEQ ID No. 1], where: o XI is any residue such as S; o X2 is either F or N; o X3, X4, X5 are each the same or different natural or non-natural hydrophobic amino acid, such as Q, F, P, A, V, I , L or cyclobutyl-alanine; o X6 is a natural or non-natural aromatic amino acid, such as W, F, Y, or Naphtyl- alanine; o X7 and X8 is any residue, wherein at least one of X7 or X8 is R or N; and o X9 is any residue, such as G.

2. The peptide of claim 1 comprising the amino acid sequence SFCPQVWGNCG [SEQ ID No. 2] or SNCPQQWRYCG [SEQ ID No. 3] or SNCAQQWRYCG [SEQ ID No. 4],3. The peptide of claim 1 or 2, which is cyclic.

4. The peptide of claim 1 or 2, which is linear.

5. The peptide of any one of claims 1-4, which is derivatized with a functional moiety comprising a diagnostic moiety or a therapeutic moiety.

6. The peptide of claim 5 wherein the diagnostic or therapeutic moiety comprises a chelator and a diagnostic or therapeutic radionuclide.

7. The peptide of claim 6 wherein the chelator comprises h2DEDPA; l,2-bis[[(6- carboxypyridin-2-yl)methyl]amino]ethane PSMA), NOTA; DOTA; a macrocyclic chelator based on 1,4,7-Triazacyclononane (TACN), or a hybrid structure chelator such as 6-amino-l,4-diazapine-triacetate (DATA).

8. The peptide of claim 7 wherein the chelator comprises NOTA (1,4,7-triazacyclononane- 1,4,7-triacetic acid) or DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid).

9. The peptide of claim 5, wherein the chelator and diagnostic or therapeutic radionuclide comprises68Ga-NOTA,177Lu -DOTA,177Lu -NOTA,225Ac-DOTA or225Ac-NOTA.

10. The peptide of claim 9 which is68Ga-NOTA-CP18.5.WSLEGAL\055326\00540\41785915v2 3911. The peptide of claim 5 wherein the diagnostic moiety comprises biotin, copper-DOTA, biotin-PEG3, aminooxyacetate,19FB,18FB, FITC-PEG3,64Cu DOTA,68Ga DOTA,68Ga NOTA,18F, A118F NOTA,64Cu,68Ga,89Zr,1241,86Y,94mTc,nC and76Br.

12. The peptide of any one of claims 5-8 comprising a therapeutic moiety which comprises 177LU or225Ac.

13. The peptide of claim 5 wherein the diagnostic moiety comprises an imaging moiety14. A method of imaging a carcinoma in a mammal, comprising the step of administering a peptide having a diagnostic moiety of any one of claims 5-11 or 13 to the mammal and detecting the diagnostic moiety.

15. The method of claim 14 wherein the diagnostic moiety is detected or imaged using PET or SPECT.

16. The method of claim 14 or 15 which is a carcinoma of the thyroid, GIST, colon, breast, sarcoma, glioblastoma, or lymphoma.

17. The method of claim 14, 15 or 16, wherein the peptide is68Ga-NOTA-CP18.5.

18. A method of treating a carcinoma in a mammal, comprising the step of administering a peptide of any one of claims 5-9 or 12 to a mammal having a carcinoma which overexpresses PDGFRA.

19. The method of claim 18 which is a carcinoma of the thyroid, GIST, colon, breast, sarcoma, glioblastoma, or lymphoma.

20. The method of claim 18 or 19 wherein the peptide comprises177Lu -NOTA-CP18.5, or 225AC-NOTA-CP18.5.

21. The method of any one of claims 18-20, further comprising a treatment with a tyrosine kinase inhibitor.WSLEGAL\055326\00540\41785915v2 40

Images