The 64CuCu-PTSM radiopharmaceutical, pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II), is suitable for use in microPET and autoradiographic imaging to assess regional tissue perfusion in ...small animal models. We report here an approach to synthesis and formulation of the 64CuCu-PTSM radiopharmaceutical at the high concentrations required for use in imaging with rodent models of human disease.
The 64CuCu-PTSM radiopharmaceutical was prepared at small volumes by addition of the H2PTSM ligand to acetate-buffered 64Cucopper chloride, followed by solid phase extraction to isolate and purify the product, which was then recovered and formulated in 2-mL normal saline containing 5% ethanol and 5% propylene glycol. Results. The 64CuCu-PTSM radiopharmaceutical has been produced over the range of 0.41–1.85 GBq (11–50 mCi) 64CuCu-PTSM in the 2.0-mL final product volume. Radiochemical purity of the 64CuCu-PTSM radiopharmaceutical product averaged 99.8 ± 0.4% (n = 64), with the final formulated product produced at an 83 ± 5% radiochemical yield.
The approach to 64CuCu-PTSM synthesis and formulation has proven to be reliable and robust, supporting radiopharmaceutical delivery at the high concentrations required for PET studies in mouse and other rodent models.
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•64CuCu-PTSM prepared in a formulation suitable for small rodent models.•Rapid and reliable synthesis producing radiopharmaceutical in range of 0.2–0.9 GBq/mL.•64CuCu-PTSM product delivered with high radiochemical purity (99.8 ± 0.4%; n = 64).•Allows microPET or autoradiographic imaging to map regional blood flow.
Traditional quantitative perfusion imaging methods require complex data acquisition and analysis strategies; typically require ancillary arterial blood sampling for measurement of input functions; ...are limited to single organ or tissue regions in an imaging session; and because of their complexity, are not well suited for routine clinical implementation in a standardized fashion that can be readily repeated across diverse clinical sites. The whole-body perfusion method described in this chapter has the advantages of on-demand radiotracer production; simple tissue pharmacokinetics enabling standardized estimation of perfusion; short-lived radionuclides, facilitating repeat or combination imaging procedures; and scalability to support widespread clinical implementation. This method leverages the unique physiological characteristics of radiolabeled copper(II) bis(thiosemicarbazone) complexes and the detection sensitivity of positron emission tomography (PET) to produce quantitatively accurate whole-body perfusion images. This chapter describes the synthesis of ethylglyoxal bis(thosemicarbazonato)copper(II) labeled with copper-62 (
CuCu-ETS), its unique physiological characteristics, a simple tracer kinetic model for estimation of perfusion using image-derived input functions, and validation of the method against a reference standard perfusion tracer. A detailed description of the methods is provided to facilitate implementation of the perfusion imaging method in PET imaging facilities.
Purpose
This study was undertaken to evaluate radiation dosimetry for the prostate-specific membrane antigen targeted
68
GaGa-P16-093 radiopharmaceutical, and to initially assess agent performance ...in positron emission tomography (PET) detection of the site of disease in prostate cancer patients presenting with biochemical recurrence.
Procedures
Under IND 133,222 and an IRB-approved research protocol, we evaluated the biodistribution and pharmacokinetics of
68
GaGa-P16-093 with serial PET imaging following intravenous administration to ten prostate cancer patients with biochemical recurrence. The recruited subjects were all patients in whom a recent
68
GaGa-PSMA-11 PET/X-ray computed tomography (CT) exam had been independently performed under IND 131,806 to assist in decision-making with regard to their clinical care. Voided urine was collected from each subject at ~ 60 min and ~ 140 min post-
68
GaGa-P16-093 injection and assayed for Ga-68 content. Following image segmentation to extract tissue time-activity curves and corresponding cumulated activity values, radiation dosimetry estimates were calculated using
IDAC Dose 2.1
. The prior
68
GaGa-PSMA-11 PET/CT exam (whole-body PET imaging at 60 min post-injection, performed with contrast-enhanced diagnostic CT) served as a reference scan for comparison to the
68
GaGa-P16-093 findings.
Results
68
GaGa-P16-093 PET images at 60 min post-injection provided diagnostic information that appeared equivalent to the subject’s prior
68
GaGa-PSMA-11 scan. With both radiopharmaceuticals, sites of tumor recurrence were found in eight of the ten patients, identifying 16 lesions. The site of recurrence was not detected with either agent for the other two subjects. Bladder activity was consistently lower with
68
GaGa-P16-093 than
68
GaGa-PSMA-11. The kidneys, spleen, salivary glands, and liver receive the highest radiation exposure from
68
GaGa-P16-093, with estimated doses of 1.7 × 10
−1
, 6.7 × 10
−2
, 6.5 × 10
−2
, and 5.6 × 10
−2
mGy/MBq, respectively. The corresponding effective dose from
68
GaGa-P16-093 is 2.3 × 10
−2
mSv/MBq.
Conclusions
68
GaGa-P16-093 provided diagnostic information that appeared equivalent to
68
GaGa-PSMA-11 in this limited series of ten prostate cancer patients presenting with biochemical recurrence, with the kidneys found to be the critical organ. Diminished tracer appearance in the urine represents a potential advantage of
68
GaGa-P16-093 over
68
GaGa-PSMA-11 for detection of lesions in the pelvis.
•Presurgical PSMA-PET appeared useful as a tool for surgical planning.•Up to 30% of patients had a recommended treatment change to nerve-sparing surgery.•Both PSMA-PET tracers, 68Ga-PSMA-11 and ...68Ga-P16-093 performed similarly.
Incontinence and impotence occur following radical prostatectomy due to injury to nerves and sphincter muscle. Preserving nerves and muscle adjacent to prostate cancer risks positive surgical margins. Advanced imaging with MRI has improved cancer localization but limitations exist.
To measure the accuracy for assessing extra-prostatic extension at nerve bundles for 2 PSMA-PET tracers and to compare the PET accuracy to standard-of-care predictors including MRI and biopsy results.
We studied men with PSMA-targeted PET imaging, performed prior to prostatectomy in men largely with intermediate to high-risk prostate cancer, and retrospectively evaluated for assessment of extra-prostatic extension with whole-mount analysis as reference standard. Two different PSMA-PET tracers were included: 68Ga-PSMA-11 and 68Ga-P16-093. Blinded reviews of the PET and MRI scans were performed to assess extra-prostatic extension (EPE). Sensitivity and specificity for extra-prostatic extension were compared using McNemar's Chi2.
Pre-operative PSMA-PET imaging was available for 71 patients with either 68Ga-P16-093 (n = 25) or 68Ga-PSMA-11 (n = 46). There were 24 (34%) with pT3a (EPE) and 16 (23%) with pT3b (SVI). EPE Sensitivity (87% vs. 92%), Specificity (77% vs. 76%), and ROC area (0.82 vs. 0.84) were similar between P16-093 and PSMA-11, respectively (P = 0.87). MRI (available in only 45) found high specificity (83%) but low sensitivity (60%) for EPE when using a published grading system. MRI sensitivity was significantly lower than the PSMA-PET (60% vs. 90%, P = 0.02), but similar to PET when using a >5 mm capsular contact (76% vs. 90%, P = 0.38). A treatment change to “nerve sparing” was recommended in 21 of 71 (30%) patients based on PSMA-PET imaging.
Presurgical PSMA-PET appeared useful as a tool for surgical planning, changing treatment plans in men with ≥4+3 or multi-core 3+4 prostate cancer resulting in preservation of nerve-bundles.
(68)GaGa-DOTA-NOC was produced under an Expanded Access IND for 174 clinical PET/CT studies to evaluate patients with neuroendocrine tumors. Production employed either the TiO2-based Eckert & Ziegler ...(EZAG) (68)Ge/(68)Ga-generator (with fractionated elution), or the SiO2-based ITG (68)Ge/(68)Ga-generator. In both cases, (68)GaGa-DOTA-NOC was reliably produced, without pre-synthesis purification of the(68)Ga generator eluate, using readily-implemented manual synthesis procedures. (68)GaGa-DOTA-NOC radiochemical purity averaged 99.2±0.4%. Administered (68)Ga dose averaged 181±22 MBq, and administered peptide mass averaged 43.2±5.2µg (n=47) and 23.9±5.7µg (n=127), respectively, using the EZAG and ITG generators. At dose expiration, (68)Ge breakthrough in the final product averaged 2.7×10(-7)% and 5.4×10(-5%) using the EZAG and ITG generators, respectively.
The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including delivery of radiolabeled folate–chelate conjugates for diagnostic imaging. This review ...surveys the growing literature on tumor imaging with radionuclide agents targeted to the folate receptor. Successful folate-receptor targeting has been reported, both in vitro and in vivo, using a variety of radionuclides that are suitable for clinical diagnostic imaging (
67Ga,
111In,
99mTc,
66Ga, and
64Cu). While none of these agents has, to date, been demonstrated to have clinical efficacy as a diagnostic tool, existing data indicates that it is feasible to noninvasively assess (at least qualitatively) tissue folate receptor levels by external radionuclide imaging.
A convenient method is described for compounding
68GaGa-MAA (MAA=macroaggregated human serum albumin) with the eluate of a commercially available TiO
2-based
68Ge/
68Ga generator. The final
...68GaGa-MAA product was obtained with an 81.6±5.3% decay-corrected radiochemical yield and a radiochemical purity of 99.8±0.1% (
n=5). Microscopic examination showed the
68GaGa-MAA product to remain within the original particle size range. The entire procedure, from generator elution to delivery of the final
68GaGa-MAA suspension, could be completed in 25
min. Only 4.4±0.9% of the total
68Ge breakthrough remaining associated with the final
68GaGa-MAA product. The procedure allows reasonably convenient preparation of
68GaGa-MAA in a fashion that can be readily adapted to sterile product compounding for human use.
Folate-conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress folate receptors. In a previous study, folic acid was linked through its γ-carboxyl group ...to deferoxamine (DF), and the 67Ga-labeled complex (67GaDF−folate) was examined for in vivo tumor targeting efficiency in athymic mice with a human tumor cell implant. Although superb tumor-to-background contrast was obtained, slow hepatobiliary clearance would compromise imaging of abdominal tumors such as ovarian cancer. In the present study, folic acid was conjugated to an alternative chelator, diethylenetriaminepentaacetic acid (DTPA), via an ethylenediamine spacer. The desired DTPA−folate(γ) regioisomer was synthesized by two different approaches, purified by reversed phase column chromatography, and characterized mainly by analytical HPLC, mass spectroscopy, and NMR. In cultured tumor cells, uptake of 111InDTPA−folate(γ) was found to be specific for folate receptor-bearing cells, and the kinetics of uptake were similar to those of free folate and other folate-conjugated molecules. In the normal rat, intravenously administered 111InDTPA−folate(γ) was found to be rapidly excreted into the urine, giving intestinal levels of radiotracer 10-fold lower than those observed with 67GaDF−folate(γ) at 4 h. In a preliminary mouse imaging study, a folate receptor-positive KB cell tumor was readily visualized by γ scintigraphy 1 h following intravenous administration of 111InDTPA−folate(γ).
Abstract The copper(II) complex of ethylglyoxal bis(thiosemicarbazone) (Cu-ETS) was evaluated as a positron emission tomography (PET) radiopharmaceutical for assessment of regional renal perfusion. ...Methods The concordance of renal flow estimates obtained with 11- and 15-μm microspheres was confirmed in four immature farm pigs using co-injected46 Sc- and57 Co-microspheres administered into the left ventricle. With the use of both immature farm pigs ( n =3) and mature Göttingen minipigs ( n =6), regional renal radiocopper uptake following intravenous 64 CuCu-ETS administration was compared to microsphere measurements of renal perfusion. The distribution and kinetics of 64 CuCu-ETS were further studied by PET imaging of the kidneys. The rate of 64 CuCu-ETS decomposition by blood was evaluated in vitro, employing octanol extraction to recover intact 64 CuCu-ETS. Results The co-injected 11- and 15-μm microspheres provided similar estimates of renal flow. A linear relationship was observed between the renal uptake of intravenous 64 CuCu-ETS and regional renal perfusion measured using microspheres. 64 CuCu-ETS provided high-quality PET kidney images demonstrating the expected count gradient from high-flow outer cortex to low-flow medulla. When incubated with pig blood in vitro at 37°C, the 64 CuCu-ETS radiopharmaceutical was observed to decompose with a half-time of 2.8 min. Conclusion Cu-ETS appears suitable for use as a PET radiopharmaceutical for evaluation of regional renal perfusion, affording renal uptake of radiocopper that varies linearly with microsphere perfusion measurements. Quantification of renal perfusion (in ml min−1 g−1 ) with 60,61,62,64 CuCu-ETS will require correcting the arterial input function for the fraction of blood radiocopper remaining present as the intact Cu-ETS radiopharmaceutical, since the Cu-ETS chelate has limited chemical stability in blood. Rapid octanol extraction of blood samples appears suitable as an approach to capturing the actual blood concentration of 60/61/62/64 CuCu-ETS.
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