Method of imaging patient

Abstract

The present invention relates to a method of performing SPECT imagining on a patient using a radiolabeled radiopharmaceutical compound. The radiopharmaceutical compound comprises a chelator and a ligand that targets a cell.

Description

METHOD OF IMAGING PATIENTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority to United States Patent Application No 63 / 701,990, filed October 1, 2024, entitled “METHOD OF IMAGING PATIENT,” the entire disclosure of which is incorporated herein by reference in its entirety.FIELD OF DISCLOSURE

[0002] The present disclosure relates to, inter alia, a method of imaging a patient using radiopharmaceuticals or radiotheranostics for diagnosing cancer, in a subject in need thereof.BACKGROUND

[0003] Targeted radionuclide therapy (TRT) is a widely used cancer treatment option that employs radiopharmaceuticals to target and deliver ionizing radiation to kill cancer cells. TRTs have been used for cancer therapy demonstrating increased overall survival as exemplified in patients with thyroid cancer, prostate cancer, and neuroendocrine tumors. As a frontline type of current cancer therapy, TRT delivers a therapeutic dose of radiation to cancer cells using radioactive drugs (radiopharmaceuticals) labelled with radionuclides such as alpha(a)- or beta(β-) -emitting radioisotopes. TRT with a emitters (a-TRT) offers several advantages compared to β- emitters, mainly due to the delivery of high-energy a-particles (5-9 MeV) to the tumour with a short pathlength (50-100 pm) and high linear energy transfer (LET), causing less toxicity to neighbouring healthy tissues. However, radiopharmaceuticals for a-TRT cannot directly be used for imaging applications in vivo to assess their biodistribution and target binding and retention profile as crucial criteria for patient selection and dose calculation in the clinical setting. The development and application of radiopharmaceuticals combining targeted imaging and therapy, also called radiotheranostics, represent a rapidly evolving field in oncologic nuclear medicine. Ideal radiotheranostics use different radioisotopes for imaging and therapy of the same chemical element to ensure similar pharmacokinetics, metabolism and biodistribution patterns. Typical examples of ideal radionuclide pairs in radiotheranostics include64Cu / 67Cu,86Y / 90Y,124I / 131I,152Tb / 161Tb,133La / 135La and203Pb / 212Pb.

[0004] The203Pb / 212Pb radionuclide pair has recently gained much attention for developing radiotheranostics for TRT.203Pb emits Υ-photons through electron capture, allowing detection with single-photon emission computed tomography (SPECT) for diagnostic imaging, whereas212Pb decays by emitting β-particles and a-particles suitable for delivering therapeutic doses of radiation to cancer cells.

[0005] Accordingly, there is a need for developing radiotheranostics compounds, compositions, and methods for a-TRT that targets various cancers. Aspects of this disclosure are directed to meetingthese and other needs. And particularly, there is a need to develop suitable imaging protocols and to characterize the scintigraphic imaging characteristics and their implications for the clinical feasibility as theragnostic isotopes.SUMMARY OF THE INVENTION

[0006] The present invention relates to a method of performing SPECT imagining on a patient using a radiolabeled radiopharmaceutical compound. The radiopharmaceutical compound comprises a chelator and a ligand that targets a cell.BRIEF DESCRIPTION OF THE FIGURES

[0007] FIG 1 illustrates the decay chain of212Pb with maximum electron energies and alpha-particle energies.

[0008] FIGS 2A-2C illustrate 2A) custom-made phantom with a body-shaped cross section, including parts of the ribs and spine with bone -equivalent tissue used for count rate performance measurements; 2B) SPECT / CT fusion image of the cylindrical phantom fdled with 2C) CT image of the NEMA image quality phantom. Transverse slice at the level of the spheres. Background ROIs, tumor ROIs, lung insert ROE

[0009] FIG 3 illustrates the planar anterior gamma camera images of the NEMA image quality phantom fdled with203Pb and212Pb in different phantom setups (spheres without background activity, sphere-to-background activity concentration ratio 8: 1 & 4: 1) acquired with MELP and HE collimators and different energy windows.

[0010] FIG 4A-4C illustrate A) a custom-made phantom with a body-shaped cross section, including parts of the ribs and spine with bone-equivalent tissue used for count rate performance measurements. B) SPECT / CT fusion image of the cylindrical phantom fdled with C) CT image of the NEMA image quality phantom. Transverse slice at the level of the spheres. Background ROIs, tumor ROIs, lung insert ROE

[0011] FIG 5A-5D illustrate A) custom-made phantom with a body-shaped cross section, including parts of the ribs and spine with bone-equivalent tissue used for count rate performance measurements. B) SPECT / CT fusion image of the cylindrical phantom fdled with C) CT image of the NEMA image quality phantom. Transverse slice at the level of the spheres. Background ROIs, tumor ROIs, lung insert ROE

[0012] FIG. 6 illustrates SPECT images of the NEMA image quality phantom fdled with203Pb in different phantom setups (spheres without background activity, sphere-to-background activityconcentration ratio 8: 1 & 4: 1). Images were acquired with MELP and HE collimators using energy windows at 279 keV and 72 keV. Transverse slices at the level of the spheres are shown.

[0013] FIG 7 illustrates SPECT images of the NEMA image quality phantom fdled with212Pb in different phantom setups (spheres without background activity, sphere-to-background activity concentration ratio 8: 1 & 4: 1). Images were acquired with MELP and HE collimators using energy windows at 239 keV and 79 keV. Transverse slices at the level of the spheres are shown.

[0014] FIG 8 illustrates recovery coefficients as a function of sphere diameter for203Pb (left column) and212Pb (right column) determined using the NEMA image quality phantom in different phantom setups (spheres without background, sphere-to-background activity concentration ratios of 8: 1 and 4: 1) acquired with MELP and HE collimators and different energy windows.DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides in certain embodiments SPECT imaging protocols using radiopharmaceutical compounds that are labeled or complexed with Pb-203 (203Pb) or Pb-212 (212Pb). The photon images are typically captured using a gamma camera (such as SPECT or SPET) that creates 3D images of organs and tissues by detecting gamma rays emitted by the radioactive tracer (radionuclide complexed with a radiopharmaceutical compound). In one embodiment of the invention, the images are captured using a SPECT (Single-Photon Emission Computed Topography) scan. SPECT scans may be combined with CT scans (SPECT / CT) to provide both functional (SPECT) and structural (CT) information from a single session.

[0016] The radiopharmaceutical compounds that can be used in the present invention include any radiopharmaceutical compounds that are complexed with a radionuclide with or without the use of chelator. In one embodiment, the radiopharmaceutical compound comprises a chelator, and the chelator is complexed with a radionuclide, for example, Pb-203 or Pb-212. It is well known to a person skilled in the art that a chelatorthat is capable of complexing Pb-203 or Pb-212 can be linked (conjugated) to a binding moiety (ligand) that targets a specific cellular molecule. A number of such cellular molecules have been published, including but not limited to PSMA, GRPR, FAP, MC1R, SSTR2, CCK2R, NTSR1, CAIX, ACP3, and CXCR4. The chelator can be DOTA (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid), DOTA-NHS-ester, p-SCN-Bn-DOTA (C-DOTA), DOTAGA (2-[ 1,4, 7, 10-Tetraazacyclododecane] -pentanedioic acid), DOTAGA-anhydride, DO2A (4,1 l-bis(carboxymethyl)-l, 4,8,1 l-tetraazabicyclo[6.6.2]hexadecan), CB-DO2A (4,10- bis(carboxymethyl)- 1 ,4,7, 10-tetraazabicyclo[5.5 ,2]tetradecane), DPDP (N,N'- dipyridoxylethylendiamine-N,N'-diacetate-5,5'-bis(phosphat)), ITC-MX (1-p-Isothiocyanato-benzyl- methyl -diethylenetriaminepentaacetic acid), TCMC ( 1,4, 7,10-tetrakis(carbamoyhnethyl)- 1,4, 7,10- tetraazacyclododecane), p-SCN-Bn-TCMC (S-2-(4-Isothiocyanatobenzyl)- 1 ,4,7, 10-tetraaza- 1,4,7,10- tetra(2-carbamoylmethyl)cyclododecane), 3p-C-DEPA (2-[(carboxymethyl)]-[5-(4-nitrophenyl-l-[4,7, 10-tris-(carboxymethyl)- 1 ,4,7, 10-tetraazacyclododecan- 1 -yl]pentan-2-yl)-amino]acetic acid), 3p- C-DEPA-NCS (2,2,A<,2,A>-(10-(2-(bis(carboxymethyl)amino)-5-(4-isothiocyanatophenyl)pentyl)- l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid), p-NH2-Bn-Oxo-DO3A (l-Oxa-4,7,10- tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TETA (1,4,8,11- tetraazacyclotetradecane 1,4,8,11-tetraacetic acid), BAT (bis-amino-bis-thiol), p-NH2-Bn-TE3A (2- (4-aminobenzyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triacetic acid), CDTA (cyclohexyl- 1,2- diaminetetraacetic acid), CPTA (4-(l,4,8,l l-tetraazacyclotetradec-l-yl)-methylbenzoic acid), C- TETA, CB-TE2A (4,1 l-bis-(carboxymethyl)-l,4,8,l 1- tetraazabicyclo[6.6.2]-hexadecane), CB- TE1A1P (l,4,8,l l-tetraazabicyclohexadecane-4-acetic acid-l l-methanephosphonic acid), CB-TE2P (1,4, 8,1 l-tetraazacyclotetradecane-l,8-di(methanephosphonic acid)), MM-TE2A, DM-TE2A, TE2A (4,1 l-bis(carboxymethyl)- 1,4, 8,11 -tetraaza- bicyclo[6.6.2]hexadecane), TMT (terpyridine- bis(methyleneamine) tetraacetic acid), TRITA (l,4,7,10-tetraazacyclotridecan-N,N',N",N"'-tetraacetic acid), TTHA (triethylenetetraaminehexaacetic acid), Diamsar (1,8-Diamino-3,6,10,13,16,19- hexaazabicyclo [6,6,6] -eicosane), SarAr ( 1 -N-(4-Aminobenzyl)-3 ,6, 10,13,16,19- hexaazabicyclo[6.6.6]- eicosane- 1,8-diamine), AmBaSar, BaBaSar, NOTA (1,4,7-triazacyclononane- 1,4,7-triacetic acid), p-SCN-Bn-NOTA (2-S-(4-Isothiocyanatobenzyl)-l,4,7-triazacyclononane-l,4,7- triacetic acid), NODA (l,4,7-triazacyclononane-l,4-diiacetic acid), NODASA (1,4,7- triazacyclononan-1 -succinic acid-4, 7-diacetic acid), NODAGA (l-(l-carboxy-3-carboxypropyl)-4,7- (carboxy)-l,4,7-triazacyclononane), NETA ({4-[2-(bis- carboxymethylamino)-ethyl]-7- carboxymethyl-[l,4,7]triazonan-l-yl}-acetic acid), NETA-monoamide, C-NE3TA-NCS (7-[2- ({carboxymethyl}[{4-isothiocyanatophenyl}methyl]amino)ethyl]-l,4,7-triazacyclononane-l,4- diacetic acid), C-NETA-NCS (4-isothiocyanatobenzyl-l-oxa-4,7,10-triazacyclododecane-N,N',N"- triacetic acid), 3p-C-NETA (4-[2-(bis-carboxymethylamino)-5-(4-nitrophenyl)-entyl])-7- carboxymethyl-triazonan-l-yl acetic acid), TACN-TM (N,N',N"-tris(2- mercaptoethyl)-l,4,7- triazacyclononane), DTPA (diethylenetriaminepentaacetic acid), p-SCN-Bn-DTPA, crown (2, 2', 2", 2"'- (l,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid), MACROPA (4- amino-6-[ [ 16-[(6-carboxypyridin-2-yl)methyl] -1,4,10,13 -tetraoxa-7, 16- diazacyclooctadec-7 - yl]methyl]pyridine-2 -carboxylic acid), MACROPA-NCS, pypa, py4pa (6,6'-(((azanediylbis(ethane- 2,1 -diyl) )bis((carboxymethyl)azanediyl))bis(methylene)) dipicolinic acid), noneunpa (6,6'- (((oxybis(ethane-2, 1 -diyl))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid), DOTAM (2,2',2",2"'-(l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetamide), DO3AM (2-(4,7,10- tris(2-amino-2 -oxoethyl)- 1,4, 7, 10-tetraazacyclododecan- l-yl)acetic acid), DOTPI (1,4,7,10- tetraazacyclododecane-1,4,7, 10-tetrakis[methylene(2-carboxyethylphosphinic acid)]), S-2-(4- isothiocyanatobenzyl)-l,4,7,10- tetraazacyclododecane tetraacetic acid, mas3 (mercaptoacetyltriserine), and derivatives thereof.

[0017] Tn the process, a patient is administrated with the radioactive tracer (radiopharmaceutical compound complexed with a radionuclide) which binds to cells or organs. The radiolabeled compoundthen emits single gamma rays. Tire SPECT or other camera rotates around the patient to capture the emitted gamma rays and convert them into signals. A computer then uses these signals to reconstruct a 3D image showing the distribution of the tracer within the body. 'The images may be acquired using a scanner, such as a SPECT / CT scanner. The scanner uses a collimator which configures the rays produced into a parallel beam. For purposes of the present invention, either a high-energy (HE) collimator or medium-energy low-penetration (MELP) collimator may be used. Hie HE collimator accepts and guides only gamma photons with high energy (typically > 250-500 keV) while rejecting lower-energy photos. The MELP collimator is used to image radioisotopes with medium -energy photons (typically between 150-400 keV). It was determined that low-energy collimators were considered to be inappropriate for use in the invention due to the relatively high photon energies of both the isotopes and progeny of the radionuclides used in the invention.

[0018] The energy windows for use in the invention depend upon the energy spectra of the radionuclides used. In one embodiment of the invention, for?0 :Pb a photopeak window is defined at 279 kdV (20% width with adjacent upper and lower scatter windows of 10% at 237 keV and 321 keV. In another embodiment, for the detection of20iPb characteristic X-rays was set to 72 keV (40% width) with adjacent scatter windows of 20% at 50 keV and 94 keV. In another embodiment, the2;2Pb photopeak window is centered at 239 keV (20% width) with two adjacent scatter windows of 10% at 209 keV and 269 keV. In another embodiment, an energy window for 212Pb X-rays is set to 79 keV (40% width) with upper and lower scatter windows of 20% centered at 55 keV and 104 keV.Hie sensitivity is then measured based on using interferometry for monitoring the changes in beam pointing using methods known in the art. such as a tillable line source. The sensitivities are calculated for each energy window as the total number of counts in the field of view (FOV) divided by the acquisition time and the measured activity.

[0019] Using the materials and methods in accordance with the invention surprisingly provide substantially higher and better sensitivity than prior methods and well as quantitatively and qualitatively better image quality.

[0020] The following examples are offered to illustrate but not limit the invention. Thus, it is presented with the understanding that various formulation modifications as well as method of delivery modifications may be made and still are within the spirit of the invention.EXAMPLESMethods

[0021] Physical properties, production, and activity measurements of203Pb and212Pb

[0022] The isotope203Pb (ti / 2=51.9 h) decays by electron capture to stable thallium-203 (2O3T1), emitting 279 keV photons suitable for scintigraphic imaging. It can be produced via the205Tl(p,3n)203Pb reaction by irradiating enriched2O5T1 targets with high-energy protons

[0035] . The203Pb used for the measurementsin this study was obtained from the Medical Isotope and Cyclotron Facility at the University of Alberta (Edmonton, AB, Canada). The beta-emitter212Pb decays with a half-life of 10.6 h via the alpha-emitters212Bi and212Po ultimately to stable208Pb (Fig. 1). In addition to alpha- and beta-emissions, several photons and characteristic X-rays are emitted by212Pb and its progeny (Table 1).212Pb can be produced from radium-224 (224Ra) using an isotope generator. For this study, a224Ra / 212Pb generator (VMT-a- GEN) manufactured by Perspective Therapeutics, Inc. (Coralville, IA, USA) was used. Radionuclide purity of both isotopes was assessed by gamma spectroscopy using a high purity germanium (HPGe) detector (Canberra Industries, Meriden, CT, USA). Radioactivity measurements for the experiments in this study were performed using a dose calibrator (ISOMED 2010, NuviaTech Healthcare, Germany) calibrated for203Pb and212Pb.

[0023] SPECT / CT camera characteristics and energy window definition

[0024] All images were acquired using a dual-head Symbia Intevo 6 SPECT / CT scanner (Siemens Healthineers, Erlangen, Germany) with 3 / 8 inch Nal(Tl) crystals. The rectangular field of view (FOV) was 53.5 cm x 38,7 cm. Two types of collimators, medium-energy low-penetration (MELP) collimators (hole length: 40.64 mm, septal thickness: 1.14 mm, hole diameter: 2.94 mm) and high-energy (HE) collimators (hole length: 59.7 mm, septal thickness: 2.0 mm, hole diameter: 4.0 mm), were evaluated for both isotopes. The use of low-energy collimators was considered inappropriate due to the relatively high photon energies of both isotopes and the high-energy emissions of the212Pb progeny. The energy windows were selected based on the emission data (Table 1) and the energy spectra of203Pb and212Pb. For203Pb, a photopeak window was defined at 279 keV (20 % width) with adjacent upper and lower scatter windows of 10 % at 237 keV and 321 keV. An additional energy window for the detection of203Pb characteristic X-rays was set to 72 keV (40 % width) with adjacent scatter windows of 20 % at 50 keV and 94 keV. The212Pb photopeak window was centered at 239 keV (20 % width) with two adjacent scatter windows of 10 % at 209 keV and 269 keV. Another energy window for the212Pb X- rays was set to 79 keV (40 % width) with upper and lower scatter windows of 20 % centered at 55 keV and 104 keV.Table 1: Gamma and X-ray emission data for203Pb and212Pb and its daughter nuclides212Bi,212Po and2O8T1. Photon energies with emission probabilities greater than 1 % are included [36-38]

[0025] Sensitivity and count rate performance

[0026] Sensitivity measurements were performed using a fillable line source (length 18 cm) placed in the center of the FOV without attenuation and scatter with activities of 10.3 MBq and 9.9 MBq for203Pb and212Pb, respectively. Planar images were acquired for 5 min on a 256 x 256 matrix with MELP and HE collimators. The source-detector distance was set to 10 cm. Sensitivities were calculated for each energy window as the total number of counts in the FOV divided by the acquisition time and the measured activity.

[0027] The count rate linearity and dead time effects were analyzed as a function of the amount of activity measured. An activity-filled vial was placed in a hole at the center of a custom-made phantom. The phantom has a body-shaped cross section (diameter 30 cm, width 8 cm), including parts of the ribs and spine with bone-equivalent tissue (Fig. 2a) to simulate patient attenuation and scattering conditions. Activities ranged from 18 MBq to 1659 MBq for203Pb and 5 MBq to 290 MBq for212Pb. Planar images were acquired for 2 min on a 256 x 256 matrix. Anterior and posterior detector-phantom center distances were set to 22 cm and 17 cm, respectively. For data analysis, the counts in the photopeak window were plotted against the activity in the phantom. For each isotope, energy window and collimator, a data fit was performed according to the paralyzable detector model (PDM) as follows:C(A) = a - A - e~T a A(1) where C is the measured count rate, A is the activity at scan time, a describes the linear detector performance and r is the detector dead time. Data points with a decreasing count rate were not fitted. The activity where the count rate begins to decrease according to the PDM fit was defined as themaximum quantifiable activity. Activities at 10 % and 20 % count rate loss were calculated. In addition, energy spectra were measured and analyzed for each acquisition.

[0028] Quantitative and qualitative evaluation of image qualityPhantom setups

[0029] The torso-shaped NEMA image quality (IQ) phantom, containing a fillable background compartment, six fillable coplanar spheres (inner diameter = 10, 13, 17, 22, 28, and 37 mm), and a cylindrical lung insert, was used to evaluate the image quality and spatial resolution. It was filled with three different sphere-to-background activity concentration ratios to resemble clinical setups. The phantom was measured with activity in the six spheres only to mimic bone metastases, which are characterized by small activity spots with low background activity. Spheres and the background compartment were filled to mimic liver metastases with different tumor-to-background ratios. Sphere- to-background activity concentration ratios of 4: 1 and of 8: 1 were used. The phantom was filled with 203Pb or212Pb with an activity concentration of approximately 40 kBq / mL in the spheres. The activity concentration in the background compartment was approximately 5 kBq / mL or 10 kBq / mL. The actual activity concentrations, sphere-to-background activity concentration ratios, and the total activity in the phantom at the time of imaging are shown in Table 2.Table 2: Information on the measurements with the NEMA image quality phantom filled with203Pb and 212Pb in different phantom setups (spheres without background; sphere-to-background activity concentration ratios 8: 1 and 4: 1).Planar imaging of the NEMA IQ phantom

[0030] Planar anterior and posterior images were acquired for each phantom setup to evaluate the planar scintigraphic imaging characteristics of203Pb and212Pb. Imaging was performed with an acquisition time of 5 min on a 256 x 256 matrix for each collimator and for the photopeak and the characteristic X-ray energy windows. The phantom was rotated and positioned in such a way that all the spheres could be imaged. The images were visually evaluated for contrast, image noise, and the detectability of the spheres.SPECT / CT acquisition and image reconstruction

[0031] All SPECT data was acquired over 360° with 120 projections (60 per detector head, 30 s per projection) on a 256 x 256 matrix using a body contouring orbit and step-and-shoot mode. The SPECT scan was followed by a low-dose CT scan (130 kV, 20 mAs, 2.5 mm slice thickness), which was used for attenuation correction. Images were reconstructed to a voxel size of 2.4 x 2.4 x 2.4 mm3using the 3D OSEM algorithm (Flash 3D; Siemens Healthineers) with 16 iterations and 8 subsets. Postreconstruction Gaussian filtering of 9 mm and 12 mm was applied for203Pb and212Pb, respectively. The larger Gaussian filter was chosen for212Pb due to the lower gamma emission probability and therefore lower count statistics and expected relatively higher image noise. Scatter correction was performed using the triple energy window method

[0039] to correct for down-scattered high-energy photons. The acquisition times were adjusted over time according to the respective half-life to obtain comparable count statistics.Image analysis

[0032] The reconstructed SPECT images were evaluated in terms of contrast recovery, image noise, lesion detectability, relative count error in the lung insert, and spatial resolution. The six hot spheres were segmented using spherical volumes of interest (VOI) with a diameter equal to the inner diameter of each sphere. The VOIs were centered using the CT. Three cylindrical VOIs (45 mm diameter, 150 mm length) were defined in the phantom background (Fig. 2c). The lung insert was delineated with a cylindrical centered VOI (30 mm diameter, 130 mm length) similar to the NEMA NU 2-2018 protocol

[0040] (Fig. 2c). The contrast recovery coefficient (CRC) was calculated for each of the six hot spheres as follows:100 % (2)where Nsis the mean number of counts in the sphere VOI, NBGis the mean number of counts in the background VOIs, and R is the true sphere-to-background activity concentration ratio. The relative count error in the lung insert (AlVlung) was determined as: 100 % (3)where Mung is the mean number of counts in the lung insert VOI. To evaluate the image noise, the noise coefficient of variation (CVBG) was calculated using: 100 % (4)where <7BGis the standard deviation of all voxels within the three background VOIs. The contrast-to- noise ratio (CNR) was used to assess object detectability. It was calculated for each sphere as follows:

[0033] The tomographic spatial resolution was determined based on the analysis of radial profiles through the homogeneously filled phantom spheres in the reconstructed images according to

[0041] , The full width at half maximum (FWHM) of the point spread function was assessed using the software Rover (version 3.0.6.60h, ABX, Germany).Quantitative imaging

[0034] To perform SPECT quantification and convert counts per voxel to Bq / mL, calibration factors (CFs) were determined using a uniform cylindrical phantom (5650 mb). The phantom was filled with activity concentrations ( / ) of 17.6 kBq / ml (total activity 99.4 MBq) and 2.56 kBq / ml (total activity 14.6 MBq) for203Pb and212Pb, respectively. A large VOI was placed in the reconstructed cylinder volume to obtain the total number of counts within the VOI (Nmi). The calibration factor was determined as:CFNVOIVv0I-t-A (6) where t is the acquisition time and Gw is the volume of the VOI. Acquisition and reconstruction were performed as described previously for the other phantom measurements.

[0035] To assess the quantification accuracy, recovery coefficients (RCs) were calculated for each of the six spheres and the background compartment in the NEMA IQ phantom. The recovery coefficient was computed as:where ASPECTis the measured activity concentration and Atrueis the known activity concentration in the spheres or in the background compartment.ResultsSensitivity and count rate performance

[0036] The sensitivities measured for203Pb and212Pb for the photopeak and the characteristic X-ray windows and for the MELP and HE collimators are listed in Table 3. For203Pb, the measurements with the 72 keV characteristic X-ray energy window showed a three times higher sensitivity than the measurements with the 279 keV photopeak window. For212Pb, the measurements with the 79 keV characteristic X-ray energy window showed a slightly lower sensitivity compared to the measurements with the 239 keV photopeak window. For both isotopes, the MELP collimators showed a higher sensitivity than the HE collimators.

[0037] Fig 4 a shows the energy spectra of203Pb and212Pb acquired with MELP and HE collimators at low and high activities. In the203Pb spectra, the photopeaks at 279 keV and 401 keV and the characteristic X-rays were visible. The characteristic X-ray peak was lower for the measurements at high activities compared to the measurements at low activities. In the212Pb spectra, the photopeak at 239 keV and the characteristic X-rays were visible. In addition, the2O8T1 photopeaks at 511 keV and 583 keV could be observed. The spectra obtained at high activities show peak broadening and peak shifting and a decrease of the X-ray peak relative to the photopeak at 239 keV. In Fig. 4b, the count rate response for203Pb and212Pb measured with MELP and HE collimators in different energy windows are shown. For203Pb, there was a moderately increasing deviation from the ideal count rate with increasing activity for all measurements. The lowest activity with a 10% count loss was 899 MBq measured with the 79 keV window and the MELP collimators (Table 3). For212Pb, a progressive count rate loss could be observed with increasing activity. The activities measured for a 20 % count rate loss were very low between 20 MBq and 43 MBq (Table 3). The maximum quantifiable activities of212Pb determined from the PDM data fit were 102 MBq and 89 MBq for the MELP collimators and 193 MBq and 166 MBq for the HE collimators, measured with the 239 keV and 79 keV energy window, respectively. For both isotopes, higher count rate losses occurred for the characteristic X-ray window compared to the photopeak window and for the MELP collimators compared to the HE collimators.Table 3: Sensitivities and estimated activities at 10 % and 20 % count rate loss for the planar measurements with203Pb and212Pb.Quantitative and qualitative evaluation of image qualityPlanar imaging of the NEMA IQ phantom

[0038] Fig 3 shows the planar images of NEMA IQ phantom in all phantom setups of203Pb and212Pb. For203Pb the, images acquired with the 279 keV energy window showed a better detectability of the spheres and lower artificial counts in the activity-free lung insert than the images acquired with the characteristic X-ray window. For the measurements of203Pb without background activity, all spheres except the smallest sphere (d=10 mm) were visible. In the 8: 1 contrast images only two spheres (d > 28 mm) and in 4: 1 contrast images only the largest sphere (d = 37 mm) were detectable. In the212Pb images with activity only in the spheres, the four largest spheres (d > 17 mm) were detectable.For the measurements with background activity, only the shape of the phantom was visible and none of the spheres were detectable. The lung insert could only be distinguished from the background in the image acquired with the HE collimators and the 72 keV energy window. All acquisitions of212Pb showed a high image and background noise. The212Pb images with activity in the background compartment showed artefacts related to image non-uniformity and the photomultiplier tube (PMT) outlines were visible.SPECT / CT imaging of203Ph with different phantom setups

[0039] Fig. 5 a depicts the CRC and the CNR as a function of sphere diameter for the NEMA IQ phantom measurements of203Pb with a sphere-to-background activity concentration ratio of 8: 1. For the images acquired with the 279 keV energy window, the CRCs were slightly higher compared to the 72 keV window images. The CRCs of the largest sphere measured with the MELP collimators were 60.2 and 48.2 for the 279 keV and 72 keV window, respectively. In contrast, the CNRs were slightly lower for the 279 keV window images compared to 72 keV window images. Spatial resolution, lung count error, and image noise determined for the different phantom setups are listed in Table 4. For the279 keV energy window measurements, the spatial resolution was approximately 0.5 mm better than for the 72 keV window measurements. The MELP collimator images showed an up to 0.9 mm better resolution compared to the HE collimator. The spatial resolution was worse for the images with background activity compared to the images with activity in the spheres only. The lung count error was up to twice as high for the 72 keV window compared to the 279 keV window measurements. The image noise was slightly worse for the HE collimators compared to the MELP collimators (noise level 19.6 % vs. 17.6 %).

[0040] Fig 6 shows the reconstructed transverse images of all NEMA IQ phantom setups of203Pb acquired with MELP and HE collimators and different energy windows. All spheres were visible for the measurements with activity in the spheres only. For the images with a sphere-to-background contrasts of 8: 1 and 4: 1, the smallest sphere (d = 10 mm) was not detectable, except for the images acquired with MELP collimator in the 72 keV window, where all spheres were detectable. Higher image noise was observed in the images acquired in the 279 keV energy window compared to the 72 keV window.Table 4: Spatial resolution (FWHM), image noise (CVBG), lung count error (ANmng), and background recovery (RCBG) determined using the NEMA image quality phantom filled with203Pb and212Pb in different phantom setups (spheres without background, contrast 8: 1 and 4: 1)SPECT / CT imaging of212Pb with different phantom setups

[0041] Fig 5 b shows the CRC and the CNR as a function of sphere diameter for the NEMA IQ phantom measurements of212Pb with a contrast ratio of 8: 1. The CRCs and the CNRs were higher for the 79 keV energy window measurements compared to the 239 keV window measurements. Spatial resolution, lung count error, and image noise determined for the different phantom setups are listed in Table 4. The spatial resolution was up to 20 mm worse for the images with 4: 1 contrast compared to the images with 8: 1 contrast and spheres without background activity. For the 4: 1 contrast acquisition with the HE collimators in the 79 keV window, the spatial resolution could not be determined because the FHWM fit did not converge. The measured count errors in the lung insert were relatively high, exceeding 70 % for almost all acquisitions. The noise level was comparable between the MELP and HE collimators, but considerably lower for the 79 keV window compared to the 239 keV window (14.9 % vs. 21.8 %).

[0042] The reconstructed transverse images of all NEMA IQ phantom setups and all acquisition protocols of212Pb are shown in Fig. 7. For the acquisitions with activity only in the spheres, all spheres except the smallest sphere (d=10 mm) were clearly visible. In the 8: 1 and 4: 1 contrast images, it was difficult to distinguish the spheres from the noisy background. The images obtained with the HE collimators in the 79 keV window showed the best visibility of the spheres, with four and two of the six spheres detectable in the 8: 1 and 4: 1 contrast images, respectively. There was a higher image noise and a blurring at the edge of the phantom in the images obtained in the 239 keV energy window compared to the 79 keV window. The images with activity in the background showed a distortion of the spheres and orbit artefacts.Quantitative imaging

[0043] The calculated calibration factors for all acquisition protocols of203Pb and212Pb are presented in Table 5. The CFs were higher for the MELP collimators compared to the HE collimators and additionally higher for the characteristic X-ray energy windows compared to the photopeak windows. The CFs determined for the HE collimators and the 79 keV window are almost identical for203Pb and212Pb, although the planar sensitivities (Table 3) were different. In addition, the CFs for212Pb for the 79 keV window were up to four times higher than the CFs for the 239 keV window, despite slightly lower planar sensitivities for the 79 keV window. In Table 4, the background recovery coefficients are shown. For203Pb, the deviations of the measured activity concentration from the true activity concentration in the background were less than or equal to 5%. For212Pb, the background recovery was significantly worse and there was a large variation between the imaging protocols and phantom setups (RCUG: 0.46 up to 0.92).

[0044] The recovery curves for all NEMA IQ phantom setups measured with different acquisition protocols are shown in Fig. 8. For203Pb, the RC decreased continuously with decreasing sphere diameter. The RC curves for the measurement with MELP collimator and 279 keV window were the most similar between the different phantom setups. In contrast, the RCs for the 72 keV window increased for the 8: 1 and 4: 1 contrast setups compared to the setup with activity in the spheres only. For the212Pb measurements without background activity, the 239 keV window images showed higher RCs than the 79 keV window images. In contrast, for the measurements with background activity, the 239 keV window images showed lower RCs than the 79 keV window images. In addition, the RCs of the three smallest spheres were similar or increased for the measurements with background activity.Table 5: Calibration factors determined measured a uniform cylindrical phantom filled with203Pb and212Pb.References1. 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[0045] It should be appreciated that minor dosage and formulation modifications of the composition and the ranges expressed herein may be made and still come within the scope and spirit of the present invention.

[0046] Having described the invention with reference to particular compositions, theories of effectiveness, and the like, it will be apparent to those of skill in the art that it is not intended that the invention be limited by such illustrative embodiments or mechanisms, and that modifications can be made without departing from the scope or spirit of the invention, as defined by the appended claims. It is intended that all such obvious modifications and variations be included within the scope of the present invention as defined in the appended claims. The claims are meant to cover the claimedcomponents and steps in any sequence which is effective to meet the objectives there intended, unless the context specifically indicates to the contrary.

[0047] The foregoing description has been presented for the purposes of illustration and description. It is not intended to be an exhaustive list or limit the invention to the precise forms disclosed. It is contemplated that other alternative processes and methods obvious to those skilled in the art are considered included in the invention. The description is merely examples of embodiments. It is understood that any other modifications, substitutions, and / or additions may be made, which are within the intended spirit and scope of the disclosure. From the foregoing, it can be seen that the exemplary aspects of the disclosure accomplish at least all of the intended objectives.

Claims

WHAT IS CLAIMED IS:

1. A method of performing SPECT imaging on a patient using lead-203 (203Pb) labeled radiopharmaceutical compound, wherein the method comprises using medium-energy low- penetration (MELP) collimators.

2. The method of claim 1, wherein the method further comprises selecting an energy window of 72 keV.

3. The method of claim 1, wherein the radiopharmaceutical compound comprises a chelator and a ligand that targets a cell.

4. The method of claim 3, wherein the ligand is selected from a group consisting of peptide, small molecule, antibody, or antibody fragment thereof.

5. A method of imaging or diagnosing cancer in a patient, the method comprising: a) complexing a radiopharmaceutical with a radionuclide to form a radioactive tracer; b) administering the radionuclide to a patient; c) detecting gamma rays emitted by the radioactive tracer; and d) creating images of organs and tissues captured from the gamma rays.

6. The method of claim 5 whereby the images are captured using a Single-Photon Emission Computed Topography (SPECT).

Images