Volume 99, Issue 10 -

In molecular imaging, the importance of novel longer lived positron emitters, also termed as non-standard or innovative PET radionuclides, has been constantly increasing, especially because they allow studies on slow metabolic processes and in some cases furnish the possibility of quantification of radiation dose in internal radiotherapy. Considerable efforts have been invested worldwide and about 25 positron emitters have been developed. Those efforts relate to interdisciplinary studies dealing with basic nuclear data, high current charged particle irradiation, efficient radiochemical separation and quality control of the desired radionuclide, and recovery of the enriched target material for reuse. In this review all those aspects are briefly discussed, with particular reference to three radionuclides, namely 64 Cu, 124 I and 86 Y, which are presently in great demand. For each radionuclide several nuclear routes were investigated but the ( p,n ) reaction on an enriched target isotope was found to be the best for use at a small-sized cyclotron. Some other positron emitting radionuclides, such as 55 Co, 76 Br, 89 Zr, 82m Rb, 94m Tc, 120 I, etc. , were also produced via the low-energy ( p,n ), ( p,α ) or ( d,n ) reaction. On the other hand, the production of radionuclides 52 Fe, 73 Se, 83 Sr, etc. using intermediate energy ( p,xn ) or ( d,xn ) reactions needs special consideration, the nuclear data and chemical processing methods being of key importance. In a few special cases, a high intensity 3 He- or α -particle beam could be an added advantage. The production of some potentially interesting positron emitters via generator systems, for example 44 Ti/ 44 Sc, 72 Se/ 72 As and 140 N d/ 140 Pr is considered. The significance of new generation high power accelerators is briefly discussed.

Copper-64 has found many applications in positron emission tomography (PET). Its half-life allows to use it for dosimetric studies associated to copper-67 targeted radiotherapy in cancer treatment. The use of 64 Ni( p , n ) 64 Cu nuclear reaction is known to produce 64 Cu in large amount and with a high specific activity. In this study, targets were obtained by electroplating onto a gold backing and a typical target irradiation uses 200ߙnA, 17ߙMeV protons during 30ߙmin. After irradiation, pure copper-64 is obtained using only one chromatographic column. Nickel-64 is removed in a first elution step and cobalt isotopes in a second one. The extraction yield for copper-64 is 9±23% and nickel and cobalt impurities are under the detection limit. A recovery process of nickel-64 has also been developed.

The radionuclide 89 Zr ( T 1/2 =78.4ߙh) is particularly attractive for in vivo assessment of biochemical proesses characterized by biological half times in the order of several hours. In the present study we assessed the feasibility of 89 Zr production via the 89 Y( p , n ) 89 Zr reaction. Irradiation tests were performed using a 16.5ߙMeV GE-PETtrace cyclotron. High purity (>99.9%) yttrium metallic foils (0.15ߙmm) were irradiated in a solid target station developed in our Institution. The literature cross section data of all the nuclear reactions possible in the energy range of interest were carefully studied to optimize the irradiation parameters. The irradiated target was dissolved in 1ߙN HCl and the activity of the sample was measured in a CRC-15 PET dose calibrator, setting different values for the calibration factor. The sample activity was then measured usin g a calibrated HPGe gamma ray detector. A comparison of the activity measurements allowed the evaluation of the calibration factor for the Capintec CRC-15 PET; for a 3ߙml syringe geometry, it was found 739±60. Saturation yields of 89 Zr were found to be 1150±110ߙMBq/μA for a single 0.15ߙmm thick disc irradiation ( E p =12.6→11.2ߙMeV) and 2400±220ߙMBq/μA for irradiation of two discs of total thickness 0.3ߙmm ( E p =12.6→9.5MeV). Total produced activities in the range of 200–400ߙMBq (according to target thickness) were repeatedly and safely obtained by 60ߙmin bombardments at 20ߙμA. Analysis of gamma ray spectra of all the samples showed a very high radionuclidic purity (>99.9995%).

This paper introduces a relatively novel paradigm that involves specific individual radionuclides or radionuclide pairs that have emissions that allow pre-therapy low-dose imaging plus higher-dose therapy in the same patient. We have made an attempt to sort out and organize a number of such theragnostic radionuclides and radionuclide pairs that may potentially bring us closer to the age-long dream of personalized medicine for performing tailored low-dose molecular imaging (SPECT/CT or PET/CT) to provide the necessary pre-therapy information on biodistribution, dosimetry, the limiting or critical organ or tissue, and the maximum tolerated dose (MTD), etc. If the imaging results then warrant it, it would be possible to perform higher-dose targeted molecular therapy in the same patient with the same radiopharmaceutical. A major problem that remains yet to be fully resolved is the lack of availability, in sufficient quantities, of a majority of the best candidate theragnostic radionuclides in a no-carrier-added (NCA) form. A brief description of the recently developed new or modified methods at BNL for the production of four theragnostic radionuclides, whose nuclear, physical, and chemical characteristics seem to show great promise for personalized cancer therapy are described.

The utilization of positron emission tomography (PET) is increasing due to its superior imaging quality and its ability to be used for in vivo quantification. Radionuclides that decay by positron emission can be attached to the same chelators used for radiotherapy applications in diagnosis and staging. One such isotope is 68 Ga ( T 1/2 = 68 min), which can be obtained from a long-lived generator by decay of the parent 68 Ge ( T 1/2 = 270.8 d). The availability of 68 Ga from a generator plus its ability to be stably incorporated with a variety of chelates hold promise for expanding PET utilization to facilities unable to afford their own cyclotron. In collaboration with researchers at the University of Missouri, we have developed and evaluated peptides that target the melanocortin-1 receptor and the gastrin-releasing peptide (GRP) receptor for peptide guided imaging and the rapy. The melanocortin-1 receptor is an attractive target for peptide guided melanoma imaging and therapy. The limited number of receptors per cell, approximately 900–5000, requires high specific activity radiolabeled peptide ligands to prevent target saturation and ensure optimal cellular uptake. GRP receptors are over-expressed by a variety of human cancers such as breast, lung, pancreatic and prostate tumors, and due to bombesin's toxicity, it is necessary to label it in high specific activity. Results are presented on NOTA and DOTA bifunctionalized α -MSH and bombesin peptides, highlighting the differences in specific activity, preparation time and in vivo characteristics.

Scandium isotopes ( 44 Sc, 47 Sc) are more available and their properties are convenient for either PET imaging or radiotherapy. To use them in nuclear medicine, ligands forming complexes with a high stability are necessary. Available experimental data on stability constants for complexes of ligands such as EDTA, DTPA, DOTA, NOTA and TETA with various metal ions have been published. But scandium is the exception since scarce data is available in the literature. Values of stability constants of Sc(III) with the ligands were determined by free-ion selective radiotracer extraction, complemented by 45 Sc NMR and potentiometry data. The thermodynamic stability of the Sc-complexes increases in the order TETA < NOTA < EDTA < DTPA < DOTA. The in vitro stability of the Sc(III) complexes was studied in the presence of hydroxyapatite and rat serum to estimate their in vivo stability. The most stable complex was shown to be Sc-DOTA.

Ligand L 1 , based on a pyridine scaffold, functionalized by two bis(methane phosphonate)aminomethyl groups, was shown to display a very high affinity towards Cu(II) (log K CuL =22.7) and selectivity over Ni(II), Co(II), Zn(II) and Ga(III) (Δ log K ML >4) as shown by the values of the stability constants obtained from potentiometric measurements. Insights into the coordination mode of the ligand around Cu(II) cation were obtained by UV-Vis absorption and EPR spectroscopies as well as density functional theory (DFT) calculations (B3LYP model) performed in aqueous solution. The results point to a pentacoordination pattern of the metal ion in the fully deprotonated [CuL 1 ] 6− species. Considering the beneficial thermodynamic parameters of this ligand, kinetic experiments were run to follow the formation of the copper(II) complexes, indicating a very rapid formation of the complex, appropriat e for 64 Cu complexation. As L 1 represents a particularly interesting target within the frame of 64 Cu PET imaging, a synthetic protocol was developed to introduce a labeling function on the pyridyl moiety of L 1 , thereby affording L 2 , a potential bifunctional chelator (BFC) for PET imaging.