First-in-Human PET Imaging of [18F]SDM-4MP3: A Cautionary Tale

Abstract

[¹⁸F]SynVesT-1 is a PET radiopharmaceutical that binds to the synaptic vesicle protein 2A (SV2A) and serves as a biomarker of synaptic density with widespread clinical research applications in psychiatry and neurodegeneration. The initial goal of this study was to concurrently conduct PET imaging studies with [¹⁸F]SynVesT-1 at our laboratories. However, the data in the first two human PET studies had anomalous biodistribution despite the injected product meeting all specifications during the prerelease quality control protocols. Further investigation, including imaging in rats as well as proton and carbon 2D-NMR spectroscopic studies, led to the discovery that a derivative of the precursor had been received from the manufacturer. Hence, we report our investigation and the first-in-human study of [¹⁸F]SDM-4MP3, a structural variant of [¹⁸F]SynVesT-1, which does not have the requisite characteristics as a PET radiopharmaceutical for imaging SV2A in the central nervous system.

Figure 1

120-minute static image (SUV units) for the first participant (P1), injected with [¹⁸F]SDM-4MP3, scaled to maximum observed SUV.

Figure 2

Average axial views in MNI space. (a) MRI shown for reference of SUVR, 60-90 min, centrum semiovale reference tissue, for subjects imaged with [¹⁸F]SDM-4MP3 (b, c), and [¹⁸F]SynVesT-1 (d, e).

Figure 3

Time-activity curves (SUV units) for an example human subject for [¹⁸F]SDM-4MP3 (solid line) and [¹⁸F]SynVesT-1 (dotted line). Data is from P1 and P3.

Figure 4

Example arterial blood results comparing [¹⁸F]SDM-4MP3 to [¹⁸F]SynVesT-1. (a) HPLC radiochromatogram from the 60 min discrete plasma sample, (b) parent fraction from all manual samples, (c) arterial plasma input function for [¹⁸F]SDM-4MP3. (d) HPLC radiochromatogram from the 60 min discrete plasma sample, (e) parent fraction from all manual samples, (f) arterial plasma input function for [¹⁸F]SynVesT-1.

Figure 5

Preclinical comparison of [¹⁸F]SDM-4MP3 and [¹⁸F]SynVesT-1 in rats. (a) Whole-brain time activity curves from 0-120 min postinjection. Blocking study data from [¹⁸F]SynVesT-1 was acquired 15 min following injection of 30 mg/kg levetiracetam, summed 120 min images showing uptake of (b) [¹⁸F]SDM-4MP3, (c) [¹⁸F]SynVesT-1, and (d) [¹⁸F]SynVesT-1 under levetiracetam blocking condition.

Figure 6

HPLC chromatograms (a) and mass spectrometry (MS) analysis (b) from precursors obtained from ABX and Yale. Precursor from an alternative commercial supplier (PharmaSynth) was also tested but was not appreciably different from the lot obtained from Yale (data not shown). The retention times for both samples were 3.30 min (ABX) and 3.31 min (Yale). The fragmentations seen in the mass spectra are similar, albeit with differing intensities, m/z 449.3 [M+H]⁺ and m/z 490.3 and the [M+CH₃CN+H]⁺ signals are clearly detectable in both mass spectra.

Figure 7

¹³C and ¹H NMR spectra of precursors obtained from ABX and Yale (aromatic region shown with discrepancies outlined in red). Annotated protons for the pyridine ring for both precursors shown on the right. Precursor lot from PharmaSynth was also tested but was not appreciably different from the Yale lot (data not shown).

Figure 8

(a) Simplified synthesis route of the precursors by Yale and PharmaSynth and radiosynthesis of [¹⁸F]SynVesT-1 ([¹⁸F]SDM-8). Nitrogen in pyridinyl ring is shown in blue. (b) Simplified synthesis route of the precursor by ABX and radiosynthesis of [¹⁸F]SDM-4MP3. Differentiating pyridinyl nitrogen is shown in green. Reaction conditions for radiosynthesis: Cu(OTf)₂, pyridine, [¹⁸F]KF, DMAc, 110°C, 20 min.